Substituted triazole derivatives as oxytocin antagonists

ABSTRACT

The present invention relates to substituted triazoles of formula (I), uses thereof, processes for the preparation thereof and compositions containing said compounds. These inhibitors have utility in a variety of therapeutic areas including sexual dysfunction.

This application is a continuation of U.S. application Ser. No.13/478,384, filed on May 23, 2012, which is a divisional of U.S.application Ser. No. 12/466,785, filed May 15, 2009, now U.S. Pat. No.8,207,198, which is a divisional of U.S. application Ser. No.11/335,940, filed Jan. 20, 2006, now U.S. Pat. No. 7,557,131, whichclaims priority from United Kingdom Application Number 0501190.3, filedJan. 20, 2005, and U.S. Application No. 60/649,892 filed Feb. 2, 2005.

The present invention relates to a class of substituted triazoles withactivity as oxytocin antagonists, uses thereof, processes for thepreparation thereof and compositions containing said inhibitors. Theseinhibitors have utility in a variety of therapeutic areas includingsexual dysfunction, particularly premature ejaculation (P.E.).

The present invention provides for compounds of formula (I):

wherein:

m is in the range of 1 to 4 and n is 1 or 2 provided that m+n is in therange of 2 to 5;

X is selected from O, NH, N(C₁-C₆)alkyl, NC(O)(C₁-C₆)alkyl,N(SO₂(C₁-C₆)alkyl), S and SO₂;

R¹ is selected from:

-   -   (i) a phenyl or naphthyl ring;    -   (ii) a 5 to 6 membered aromatic heterocyclic ring containing 1        to 3 heteroatoms independently selected from N, O and S and        N-oxides thereof;    -   (iii) a 9 to 10 membered bicyclic aromatic heterocyclic ring        containing 1 to 4 heteroatoms independently selected from N, O        and S and N-oxides thereof; and    -   (iv) 2-pyridonyl;        each of which is optionally substituted with one or more        substituents independently selected from halo, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃,        NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂, CO(C₁-C₆)alkyl,        C(O)NH(C₁-C₆)alkyl, C(O)N((C₁-C₆)alkyl)₂, C(O)OH and C(O)NH₂;

R² is selected from:

-   -   (i) H or hydroxy;    -   (ii) (C₁-C₆)alkyl, which is optionally substituted by        O(C₁-C₆)alkyl or phenyl;    -   (iii) O(C₁-C₆)alkyl, which is optionally substituted by        O(C₁-C₆)alkyl;    -   (iv) NH(C₁-C₆)alkyl, said alkyl group being optionally        substituted by O(C₁-C₆)alkyl;    -   (v) N((C₁-C₆)alkyl)₂, one or both of said alkyl groups being        optionally substituted by O(C₁-C₆)alkyl;    -   (vi) a 5 to 8 membered N-linked saturated or partially saturated        heterocycle containing 1 to 3 heteroatoms, each independently        selected from N, O and S, wherein at least one heteroatom is N        and said ring may optionally incorporate one or two carbonyl        groups; said ring being optionally substituted with one or more        groups selected from CN, halo, (C₁-C₆)alkyl, O(C₁-C₆)alkyl,        NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂, C(O)(C₁-C₆)alkyl,        C(O)NH(C₁-C₆)alkyl, C(O)N((C₁-C₆)alkyl)₂, C(O)OH, C(O)NH₂ and        C(O)OCH₂Ph; and    -   (vii) a 5 to 7 membered N-linked aromatic heterocycle containing        1 to 3 heteroatoms each independently selected from N, O and S,        wherein at least one heteroatom is N; said ring being optionally        substituted with one or more groups selected from CN, halo,        (C₁-C₆)alkyl, O(C₁-C₆)alkyl, NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂,        C(O)(C₁-C₆)alkyl, C(O)NH(C₁-C₆)alkyl, C(O)N((C₁-C₆)alkyl)₂,        C(O)OH, C(O)NH₂ and C(O)OCH₂Ph;

R³ is selected from H, (C₁-C₆)alkyl and (C₁-C₆)alkoxy(C₁-C₆)alkyl;

R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halo, hydroxy,CN, (C₁-C₆)alkyl, NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂ and O(C₁-C₆)alkyl;and

R⁸ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, CH₂OH,CH₂NH₂, CH₂NH(C₁-C₆)alkyl, CH₂N((C₁-C₆)alkyl)₂, CN, C(O)NH₂,C(O)NH(C₁-C₆)alkyl and C(O)N((C₁-C₆)alkyl)₂;

a tautomer thereof or a pharmaceutically acceptable salt, solvate orpolymorph of said compound or tautomer.

Unless otherwise indicated, alkyl and alkoxy groups may be straight orbranched and contain 1 to 6 carbon atoms and typically 1 to 4 carbonatoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, pentyl and hexyl. Examples of alkoxyinclude methoxy, ethoxy, isopropoxy and n-butoxy.

Halo means fluoro, chloro, bromo or iodo and is in particular fluoro orchloro.

A heterocycle may be saturated, partially saturated or aromatic.Examples of saturated heterocyclic groups are tetrahydrofuranyl,thiolanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,sulfolanyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, piperidinyl,pyrazolinyl, pyrazolidinyl, dioxanyl, morpholinyl, dithianyl,thiomorpholinyl, piperazinyl, azepinyl, oxazepinyl, thiazepinyl,thiazolinyl and diazapanyl. Examples of aromatic heterocyclic groups arepyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl,1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl,1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Examples of bicyclicaromatic heterocyclic groups are benzofuranyl, benzothiophenyl, indolyl,benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl and isoquinolinyl.

Ph means phenyl.

Unless otherwise indicated, the term substituted means substituted byone or more defined groups. In the case where groups may be selectedfrom a number of alternative groups, the selected groups may be the sameor different.

In one embodiment, the present invention provides for compounds offormula (I) wherein:

m is in the range of 1 to 4 and n is 1 or 2 provided that m+n is in therange of 2 to 5;

X is selected from O, NH, N(C₁-C₆)alkyl, and N(SO₂(C₁-C₆)alkyl);

R¹ is selected from:

-   -   (i) a phenyl ring;    -   (ii) a 5 to 6 membered aromatic heterocyclic ring containing 1        to 3 nitrogen atoms; and    -   (iii) 2-pyridonyl;        each of which is optionally substituted with one or more        substituents independently selected from halo, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃,        NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂, CO(C₁-C₆)alkyl,        C(O)O(C₁-C₆)alkyl, C(O)NH(C₁-C₆)alkyl, C(O)N((C₁-C₆)alkyl)₂,        C(O)OH and C(O)NH₂;

R² is selected from:

-   -   (i) H or hydroxy;    -   (ii) (C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl;    -   (iii) O(C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl;    -   (iv) NH(C₁-C₃)alkyl, said alkyl group being optionally        substituted by O(C₁-C₃)alkyl;    -   (v) N((C₁-C₃)alkyl)₂, one or both of said alkyl groups being        optionally substituted by O(C₁-C₃)alkyl;    -   (vi) a 5 to 6 membered N-linked saturated heterocycle containing        1 to 2 nitrogen atoms; said ring may optionally incorporate one        or two carbonyl groups; said ring being optionally substituted        by C(O)NH₂ or C(O)OCH₂Ph; and    -   (vii) a 5 to 6 membered N-linked aromatic heterocycle containing        1 to 3 heteroatoms each independently selected from N, O and S,        wherein at least one heteroatom is N;

R³ is selected from H, (C₁-C₆)alkyl and (C₁-C₆)alkoxy(C₁-C₆)alkyl;

R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halo, hydroxy,CN, (C₁-C₆)alkyl, NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂ and O(C₁-C₆)alkyl;and

R⁸ is selected from H, (C₁-C₃)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl, CH₂OH,CH₂NH₂, CH₂NH(C₁-C₃)alkyl, CH₂N((C₁-C₃)alkyl)₂, CN, C(O)NH₂,C(O)NH(C₁-C₃)alkyl and C(O)N((C₁-C₃)alkyl)₂;

a tautomer thereof or a pharmaceutically acceptable salt, solvate orpolymorph of said compound or tautomer.

In a further embodiment, the present invention provides for compounds offormula (I) wherein:

m is in the range of 1 to 3 and n is 1 or 2;

X is selected from O, NH, N(C₁-C₃)alkyl, and N(SO₂(C₁-C₃)alkyl);

R¹ is selected from:

-   -   (i) a phenyl ring;    -   (ii) a 5 to 6 membered aromatic heterocyclic ring containing 1        to 3 nitrogen atoms; and    -   (iii) 2-pyridonyl;        each of which is optionally substituted with one or more        substituents independently selected from halo, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃,        NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂,        O(C₁-C₆)alkyl, C(O)O(C₁-C₆)alkyl, C(O)NH(C₁-C₆)alkyl,        C(O)N((C₁-C₆)alkyl)₂, C(O)OH and C(O)NH₂;

R² is selected from:

-   -   (i) H or hydroxy;    -   (ii) (C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl;    -   (iii) O(C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl;    -   (iv) NH(C₁-C₃)alkyl, said alkyl group being optionally        substituted by O(C₁-C₃)alkyl; and    -   (v) N((C₁-C₃)alkyl)₂, one or both of said alkyl groups being        optionally substituted by O(C₁-C₃)alkyl;

R³ is selected from H, (C₁-C₆)alkyl and (C₁-C₆)alkoxy(C₁-C₆)alkyl;

R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halo, hydroxy,(C₁-C₆)alkyl and O(C₁-C₆)alkyl; and

R⁸ is selected from H, methyl, ethyl, isopropyl, methoxymethyl,methoxyethyl, CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CN, C(O)NH₂,C(O)NHCH₃, and C(O)N(CH₃)₂; a tautomer thereof or a pharmaceuticallyacceptable salt, solvate or polymorph of said compound or tautomer.

In yet a further embodiment, the present invention provides forcompounds of formula (I) wherein:

m is 1 or 2 and n is 1 or 2;

X is selected from O, NH, NCH₃ and N(SO₂CH₃);

R¹ is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, pyrazolyl and 2-pyridonyl each of which is optionallysubstituted with one to three substituents independently selected fromhalo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano,CF₃, N((C₁-C₆)alkyl)₂, C(O)N((C₁-C₆)alkyl)₂, and C(O)NH₂;

R² is selected from:

-   -   (i) H or hydroxy;    -   (ii) (C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl; and    -   (iii) O(C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl;

R³ is H or (C₁-C₃)alkyl;

R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, chloro,fluoro, hydroxy, methyl and methoxy; and

R⁸ is H or methyl;

a tautomer thereof or a pharmaceutically acceptable salt, solvate orpolymorph of said compound or tautomer.

In yet a further embodiment, the present invention provides forcompounds of formula (I) wherein:

m and n are both 1, or m and n are both 2, or m is 1 and n is 2;

X is O or NCH₃;

R¹ is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, pyrazolyl and 2-pyridonyl, each of which is optionallysubstituted with one to three substituents independently selected fromchloro, fluoro, methyl, ethyl, isopropyl, methoxy, cyano, CF₃, N(CH₃)₂,C(O)N(CH₃)₂, and C(O)NH₂;

R² is selected from H, hydroxy, methyl, methoxy and ethoxy;

R³ is H or CH₃;

R⁴ is H or methyl;

R⁵ is hydroxy or methoxy;

R⁶ and R⁷ are both H; and

R⁸ is H or methyl;

a tautomer thereof or a pharmaceutically acceptable salt, solvate orpolymorph of said compound or tautomer.

In yet a further embodiment, the present invention provides forcompounds of formula (I) wherein:

m and n are both 1, or m and n are both 2, or m is 1 and n is 2;

X is O;

R¹ is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, pyrazolyl and 2-pyridonyl, each of which is optionallysubstituted with one to three substituents independently selected fromchloro, fluoro, methyl, ethyl, isopropyl, methoxy, cyano, CF₃, N(CH₃)₂,C(O)N(CH₃)₂, and C(O)NH₂;

R² is selected from H, methyl, methoxy and ethoxy;

R³, R⁴, R⁶, R⁷ and R⁸ are H; and

R⁵ is methoxy;

a tautomer thereof or a pharmaceutically acceptable salt, solvate orpolymorph of said compound or tautomer.

In one embodiment, m is in the range of 1 to 3 and n is 1 or 2. In afurther embodiment, m is 1 or 2 and n is 1 or 2. In yet a furtherembodiment, m and n are both 1, or m and n are both 2, or m is 1 and nis 2.

In one embodiment, X is selected from O, NH, N(C₁-C₆)alkyl, andN(SO₂(C₁-C₆)alkyl). In a further embodiment, X is selected from O, NH,N(C₁-C₃)alkyl, and N(SO₂(C₁-C₃)alkyl). In yet a further embodiment, X isselected from O, NH, NCH₃ and N(SO₂CH₃). In yet a further embodiment, Xis O or NCH₃. In yet a further embodiment, X is O.

In one embodiment, R¹ is selected from:

-   -   (i) a phenyl or naphthyl ring;    -   (ii) a 5 to 6 membered aromatic heterocyclic ring containing 1        to 3 hetero atoms independently selected from N, O and S and        N-oxides thereof;    -   (iii) a 9 to 10 membered bicyclic aromatic heterocyclic ring        containing 1 to 4 nitrogen atoms; and    -   (iv) 2-pyridonyl;        each of which is optionally substituted with one or more        substituents independently selected from halo, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃,        NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂, CO(C₁-C₆)alkyl,        C(O)O(C₁-C₆)alkyl, C(O)NH(C₁-C₆)alkyl, C(O)N((C₁-C₆)alkyl)₂,        C(O)OH and C(O)NH₂.

In a further embodiment, R¹ is selected from:

-   -   (i) a phenyl ring;    -   (ii) a 5 to 6 membered aromatic heterocyclic ring containing 1        to 3 nitrogen atoms; and    -   (iii) 2-pyridonyl;        each of which is optionally substituted with one or more        substituents independently selected from halo, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃,        NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂, CO(C₁-C₆)alkyl,        C(O)O(C₁-C₆)alkyl, C(O)NH(C₁-C₆)alkyl, C(O)N((C₁-C₆)alkyl)₂,        C(O)OH and C(O)NH₂.

In yet a further embodiment, R¹ is selected from:

-   -   (i) a phenyl ring;    -   (ii) a 5 to 6 membered aromatic heterocyclic ring containing 1        to 3 nitrogen atoms; and    -   (iii) 2-pyridonyl;        each of which is optionally substituted with one or more        substituents independently selected from halo, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃,        NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂, CO(C₁-C₆)alkyl,        C(O)O(C₁-C₆)alkyl, C(O)NH(C₁-C₆)alkyl, C(O)N((C₁-C₆)alkyl)₂,        C(O)OH and C(O)NH₂.

In yet a further embodiment, R¹ is selected from:

-   -   (i) a phenyl ring;    -   (ii) a 5 to 6 membered aromatic heterocyclic ring containing 1        to 3 nitrogen atoms; and    -   (iii) 2-pyridonyl;        each of which is optionally substituted with one or more        substituents independently selected from halo, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃,        N((C₁-C₆)alkyl)₂, C(O)N((C₁-C₆)alkyl)₂, and C(O)NH₂.

In yet a further embodiment, R¹ is selected from phenyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl and 2-pyridonyl, each ofwhich is optionally substituted with one or more substituentsindependently selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃, N((C₁-C₆)alkyl)₂,C(O)N((C₁-C₆)alkyl)₂, and C(O)NH₂.

In yet a further embodiment, R¹ is selected from phenyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl and 2-pyridonyl, each ofwhich is optionally substituted with one to three substituentsindependently selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃, N((C₁-C₆)alkyl)₂,C(O)N((C₁-C₆)alkyl)₂, and C(O)NH₂.

In yet a further embodiment, R¹ is selected from phenyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl and 2-pyridonyl, each ofwhich is optionally substituted with one to three substituentsindependently selected from chloro, fluoro, methyl, ethyl, isopropyl,methoxy, cyano, CF₃, N(CH₃)₂, C(O)N(CH₃)₂, and C(O)NH₂.

In yet a further embodiment, R¹ is selected from phenyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl and 2-pyridonyl, each of which isoptionally substituted with one to three substituents independentlyselected from chloro, fluoro, methyl, ethyl, isopropyl, methoxy, cyano,CF₃, N(CH₃)₂, C(O)N(CH₃)₂, and C(O)NH₂.

In one embodiment, R² is selected from:

-   -   (i) H or hydroxy;    -   (ii) (C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl;    -   (iv) O(C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl;    -   (v) NH(C₁-C₃)alkyl, said alkyl group being optionally        substituted by O(C₁-C₃)alkyl;    -   (vi) N((C₁-C₃)alkyl)₂, wherein one or both of said alkyl groups        may be optionally substituted by O(C₁-C₃)alkyl;    -   (vii) a 5 to 6 membered N-linked saturated heterocycle        containing 1 to 2 nitrogen atoms; said ring may optionally        incorporate one or two carbonyl groups; said ring being        optionally substituted by C(O)NH₂ or C(O)OCH₂Ph; and    -   (viii) a 5 to 6 membered N-linked aromatic heterocycle        containing 1 to 3 heteroatoms each independently selected from        N, O and S, wherein at least one heteroatom is N.

In a further embodiment, R² is selected from:

-   -   (i) H or hydroxy;    -   (ii) (C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl;    -   (iii) O(C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl;    -   (iv) NH(C₁-C₃)alkyl, said alkyl group being optionally        substituted by O(C₁-C₃)alkyl; and    -   (v) N((C₁-C₃)alkyl)₂, wherein one or both of said alkyl groups        may be optionally substituted by O(C₁-C₃)alkyl.

In yet a further embodiment, R² is selected from:

-   -   (i) H or hydroxy;    -   (ii) (C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl; and    -   (iii) O(C₁-C₃)alkyl, which is optionally substituted by        O(C₁-C₃)alkyl.

In yet a further embodiment, R² is selected from H, hydroxy, methyl,methoxy and ethoxy. In yet a further embodiment, R² is selected from H,methyl, methoxy and ethoxy.

In one embodiment, R³ is H or (C₁-C₃)alkyl. In a further embodiment, R³is H or CH₃. In yet a further embodiment, R³ is H.

In one embodiment, R⁴, R⁵, R⁶ and R⁷ are each independently selectedfrom H, halo, hydroxy, (C₁-C₆)alkyl and O(C₁-C₆)alkyl. In a furtherembodiment, R⁴, R⁵, R⁶ and R⁷ are each independently selected from H,halo, hydroxy, (C₁-C₃)alkyl and O(C₁-C₃)alkyl. In yet a furtherembodiment, R⁴, R⁵, R⁶ and R⁷ are each independently selected from H,chloro, fluoro, hydroxy, methyl and methoxy. In yet a furtherembodiment, R⁴ is H or methyl; R⁵ is hydroxy or methoxy; and R⁶ and R⁷are both H. In yet a further embodiment, R⁴, R⁶ and R⁷ are H and R⁵ ismethoxy.

In one embodiment, R⁸ is selected from H, (C₁-C₃)alkyl,(C₁-C₃)alkoxy(C₁-C₃)alkyl, CH₂OH, CH₂NH₂, CH₂NH(C₁-C₅₃)alkyl,CH₂N((C₁-C₃)alkyl)₂, CN, C(O)NH₂, C(O)NH(C₁-C₅₃)alkyl andC(O)N((C₁-C₃)alkyl)₂. In a further embodiment, R⁸ is selected from H,methyl, ethyl, isopropyl, methoxymethyl, methoxyethyl, CH₂OH, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, CN, C(O)NH₂, C(O)NHCH₃, and C(O)N(CH₃)₂.

In yet a further embodiment, R⁸ is selected from H, methyl, ethyl,methoxymethyl, methoxyethyl and CN. In yet a further embodiment, R⁸ is Hor methyl. In yet a further embodiment, R⁸ is H.

It is to be understood that the invention covers all combinations ofparticular embodiments of the invention as described hereinabove,consistent with the definition of the compounds of formula (I).

Representative compounds of formula (I) are:

-   5-[3-[4-(3-fluoro-2-methylphenoxy)piperidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine;-   2-methoxy-5-{3-(methoxymethyl)-5-[4-(2-methylphenoxyl)piperidin-1-yl]-4H-1,2,4-triazol-4-yl}pyridine;-   5-[3-[4-(5-fluoro-2-methylphenoxy)piperidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine;-   5-{3-[4-(3-fluoro-2-methylphenoxy)piperidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine;-   5-[3-[4-(2-chlorophenoxyl)piperidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine;-   3-{3-[3-(4-fluoro-2-methylphenoxy)azetidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-6-methoxy-2-methylpyridine;-   5-[3-[4-(4-fluoro-2-methylphenoxy)piperidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine;-   5-{3-[4-(4-fluoro-2-methylphenoxy)piperidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine;-   2-methoxy-5-{3-methyl-5-[4-(2-methylphenoxyl)piperidin-1-yl]-4H-1,2,4-triazol-4-yl}pyridine;-   5-{3-[4-(2-chlorophenoxyl)piperidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine;-   5-[3-[4-(3,4-difluorophenoxyl)piperidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine;-   5-{3-[3-(2-ethyl-4-fluorophenoxy)azetidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine;-   5-[3-[3-(2-chloro-4-fluorophenoxy)azetidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine;-   5-{3-[4-(3,5-difluorophenoxyl)piperidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine;-   5-[3-[3-(2,3-dimethylphenoxyl)azetidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine;-   5-[3-[4-(3,5-difluorophenoxyl)piperidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine;-   5-{3-[3-(4-fluoro-2-methylphenoxy)azetidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine;-   5-{3-[3-(2,3-dimethylphenoxyl)azetidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine;-   2-methoxy-5-(3-(methoxymethyl)-5-{3-[3-(trifluoromethyl)phenoxy]azetidin-1-yl}-4H-1,2,4-triazol-4-yl)pyridine;-   5-{3-[3-(2-chloro-4-fluorophenoxy)azetidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine;-   2-methoxy-5-(3-(methoxymethyl)-5-{4-[(3-methylpyridin-4-yl)oxy]piperidin-1-yl}-4H-1,2,4-triazol-4-yl)pyridine;-   3-({1-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)-2-methylbenzonitrile;-   2-methoxy-5-{3-[4-(3-methoxy-2-methylphenoxy)piperidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}pyridine;    and-   5-[3-[3-(3-chlorophenoxyl)azetidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine;    and tautomers thereof and pharmaceutically acceptable salts,    solvates and polymorphs of said compounds or tautomers.

Pharmaceutically acceptable salts of the compounds of formula (I)comprise the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate,gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate,tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002). All references cited herein are incorporatedby reference in their entirety for all purposes.

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of three methods:

-   (i) by reacting the compound of formula (I) with the desired acid or    base;-   (ii) by removing an acid- or base-labile protecting group from a    suitable precursor of the compound of formula (I) using the desired    acid or base; or-   (iii) by converting one salt of the compound of formula (I) to    another by reaction with an appropriate acid or base or by means of    a suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein the drug and host arepresent in stoichiometric or non-stoichiometric amounts. Also includedare complexes of the drug containing two or more organic and/orinorganic components which may be in stoichiometric ornon-stoichiometric amounts. The resulting complexes may be ionised,partially ionised, or non-ionised. For a review of such complexes, see JPharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

Hereinafter all references to compounds of formula (I) includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of formula (I) ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of formula (I).

As indicated, so-called ‘pro-drugs’ of the compounds of formula (I) arealso within the scope of the invention. Thus certain derivatives ofcompounds of formula (I) which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into compounds of formula (I) having the desired activity, forexample, by hydrolytic cleavage. Such derivatives are referred to as‘prodrugs’. Further information on the use of prodrugs may be found in“Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series (T.Higuchi and W. Stella) and “Bioreversible Carriers in Drug Design”,Pergamon Press, 1987 (ed. E. B. Roche, American PharmaceuticalAssociation).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in “Design of Prodrugs” by H.Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include

(i) where the compound of formula I contains a carboxylic acidfunctionality, an ester thereof, for example, a compound wherein thehydrogen of the carboxylic acid functionality of the compound of formula(I) is replaced by (C₁-C₈)alkyl; and

(ii) where the compound of formula (I) contains a primary or secondaryamino functionality, an amide thereof, for example, a compound wherein,as the case may be, one or both hydrogens of the amino functionality ofthe compound of formula (I) is/are replaced by (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references. Moreover, certain compounds of formula (I)may themselves act as prodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites ofcompounds of formula (I), that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include

-   -   (i) where the compound of formula (I) contains a methyl group,        an hydroxymethyl derivative thereof (—CH₃→—CH₂OH):    -   (ii) where the compound of formula (I) contains an alkoxy group,        an hydroxy derivative thereof (—OR→—OH);    -   (iii) where the compound of formula (I) contains a tertiary        amino group, a secondary amino derivative thereof (—NR¹R²→—NHR¹        or —NHR²);    -   (iv) where the compound of formula (I) contains a secondary        amino group, a primary derivative thereof (—NHR¹→—NH₂);    -   (v) where the compound of formula (I) contains a phenyl moiety,        a phenol derivative thereof (-Ph→-PhOH); and    -   (vi) where the compound of formula (I) contains an amide group,        a carboxylic acid derivative thereof (—CONH₂→COOH).

Compounds of formula (I) containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of formula (I)contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where structural isomers are interconvertible viaa low energy barrier, tautomeric isomerism (‘tautomerism’) can occur.This can take the form of proton tautomerism in compounds of formula (I)containing, for example, a keto group, or so-called valence tautomerismin compounds which contain an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula (I), including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition salts wherein the counterion is optically active, for example,d-lactate or l-lysine, or racemic, for example, di-tartrate ordi-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (I) contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of isopropanol, typically from 2% to 20%, and from 0 to 5% byvolume of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture.

The present invention includes all crystal forms of the compounds offormula (I) including racemates and racemic mixtures (conglomerates)thereof. Stereoisomeric conglomerates may be separated by conventionaltechniques known to those skilled in the art—see, for example,“Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen(Wiley, New York, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the accompanying Examples and Preparations using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Also within the scope of the invention are intermediate compounds ashereinafter defined, all salts, solvates and complexes thereof and allsolvates and complexes of salts thereof as defined hereinbefore forcompounds of formula (I). The invention includes all polymorphs of theaforementioned species and crystal habits thereof.

When preparing compounds of formula (I) in accordance with theinvention, it is open to a person skilled in the art to routinely selectthe form of intermediate which provides the best combination of featuresfor this purpose. Such features include the melting point, solubility,processability and yield of the intermediate form and the resulting easewith which the product may be purified on isolation.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products or may exist in acontinuum of solid states ranging from fully amorphous to fullycrystalline. They may be obtained, for example, as solid plugs, powders,or films by methods such as precipitation, crystallization, freezedrying, spray drying, or evaporative drying. Microwave or radiofrequency drying may be used for this purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof). Generally, they will beadministered as a formulation in association with one or morepharmaceutically acceptable excipients. The term ‘excipient’ is usedherein to describe any ingredient other than the compound(s) of theinvention. The choice of excipient will to a large extent depend onfactors such as the particular mode of administration, the effect of theexcipient on solubility and stability, and the nature of the dosageform.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in “Remington'sPharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth. Formulations suitable for oral administration include solidformulations such as tablets, capsules containing particulates, liquids,or powders, lozenges (including liquid-filled), chews, multi- andnano-particulates, gels, solid solution, liposome, films, ovules, spraysand liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsulesand typically comprise a carrier, for example, water, ethanol,polyethylene glycol, propylene glycol, methylcellulose, or a suitableoil, and one or more emulsifying agents and/or suspending agents. Liquidformulations may also be prepared by the reconstitution of a solid, forexample, from a sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up from 1weight % to 80 weight % of the dosage form, more typically from 5 weight% to 60 weight % of the dosage form. In addition to the drug, tabletsgenerally contain a disintegrant. Examples of disintegrants includesodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, croscarmellose sodium, crospovidone,polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose,lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinisedstarch and sodium alginate. Generally, the disintegrant will comprisefrom 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight% of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 weight % to 5 weight % of the tablet, and glidants may comprise from0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight %to 3 weight % of the tablet. Other possible ingredients includeanti-oxidants, colourants, flavouring agents, preservatives andtaste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight %to about 90 weight % binder, from about 0 weight % to about 85 weight %diluent, from about 2 weight % to about 10 weight % disintegrant, andfrom about 0.25 weight % to about 10 weight % lubricant. Tablet blendsmay be compressed directly or by roller to form tablets. Tablet blendsor portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated. The formulation of tablets isdiscussed in “Pharmaceutical Dosage Forms: Tablets”, Vol. 1, by H.Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically pliablewater-soluble or water-swellable thin film dosage forms which may berapidly dissolving or mucoadhesive and typically comprise a compound offormula (I), a film-forming polymer, a binder, a solvent, a humectant, aplasticiser, a stabiliser or emulsifier, a viscosity-modifying agent anda solvent. Some components of the formulation may perform more than onefunction.

The compound of formula (I) may be water-soluble or insoluble. Awater-soluble compound typically comprises from 1 weight % to 80 weight%, more typically from 20 weight % to 50 weight %, of the solutes. Lesssoluble compounds may comprise a greater proportion of the composition,typically up to 88 weight % of the solutes. Alternatively, the compoundof formula (I) may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides,proteins, or synthetic hydrocolloids and is typically present in therange 0.01 to 99 weight %, more typically in the range 30 to 80 weight%.

Other possible ingredients include anti-oxidants, colorants, flavouringsand flavour enhancers, preservatives, salivary stimulating agents,cooling agents, co-solvents (including oils), emollients, bulkingagents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared byevaporative drying of thin aqueous films coated onto a peelable backingsupport or paper. This may be done in a drying oven or tunnel, typicallya combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in “Pharmaceutical Technology On-line”,25(2), 1-14, by Verma et al (2001). The use of chewing gum to achievecontrolled release is described in WO 00/35298.

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water. The preparation of parenteral formulationsunder sterile conditions, for example, by lyophilisation, may readily beaccomplished using standard pharmaceutical techniques well known tothose skilled in the art.

The solubility of compounds of formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents. Formulations for parenteral administrationmay be formulated to be immediate and/or modified release. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release. Thus compounds of the invention may beformulated as a solid, semi-solid, or thixotropic liquid foradministration as an implanted depot providing modified release of theactive compound. Examples of such formulations include drug-coatedstents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibres, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may beincorporated—see, for example, J Pharm Sci, 88 (10), 955-958, by Finninand Morgan (October 1999). Other means of topical administration includedelivery by electroporation, iontophoresis, phonophoresis, sonophoresisand microneedle or needle-free (e.g. Powderject™, Bioject™, etc.)injection. Formulations for topical administration may be formulated tobe immediate and/or modified release. Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release.

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the invention, a suitable powder base such as lactose orstarch and a performance modifier such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate, preferably the latter. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose andtrehalose.

A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μl to 100 μl. A typical formulation may comprisea compound of formula (I), propylene glycol, sterile water, ethanol andsodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example, PGLA. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from 2 to 30 mg of the compound offormula (I). The overall daily dose will typically be in the range 50 to100 mg which may be administered in a single dose or, more usually, asdivided doses throughout the day.

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate. Formulations for rectal/vaginaladministration may be formulated to be immediate and/or modifiedrelease. Modified release formulations include delayed-, sustained-,pulsed-, controlled-, targeted and programmed release.

The compounds of the invention may also be administered directly to theeye or ear, typically in the form of drops of a micronised suspension orsolution in isotonic, pH-adjusted, sterile saline. Other formulationssuitable for ocular and aural administration include ointments,biodegradable (e.g. absorbable gel sponges, collagen) andnon-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

The compounds of the invention may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration. Drug-cyclodextrin complexes, for example, are found tobe generally useful for most dosage forms and administration routes.Both inclusion and non-inclusion complexes may be used. As analternative to direct complexation with the drug, the cyclodextrin maybe used as an auxiliary additive, i.e. as a carrier, diluent, orsolubiliser. Most commonly used for these purposes are alpha-, beta- andgamma-cyclodextrins, examples of which may be found in InternationalPatent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148 andare hereto incorporated by reference without any limitation herein.

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range 50 mg to 100 mgdepending, of course, on the mode of administration and efficacy. Forexample, oral administration may require a total daily dose of from 50mg to 100 mg. The total daily dose may be administered in single ordivided doses and may, at the physician's discretion, fall outside ofthe typical range given herein. These dosages are based on an averagehuman subject having a weight of about 60 kg to 70 kg. The physicianwill readily be able to determine doses for subjects whose weight fallsoutside this range, such as infants and the elderly.

For the avoidance of doubt, references herein to “treatment” includereferences to curative, palliative and prophylactic treatment.

Processes

Compounds of general formula (I) wherein m, n, X and R¹ to R⁸ are asdescribed herein can be prepared as described in Scheme 1.

LG represents a suitable leaving group such as mesylate or tosylate andis typically mesylate. When LG is mesylate compounds of general formula(l) can be prepared as described in WO 97/25322 at p 64.

Compounds of general formula (III) can be prepared from compounds ofgeneral formula (II) by process step (i), wherein thiourea formation isachieved by reaction of compound (II) with a suitable aminopyridine inthe presence of a suitable thiocarbonyl transfer agent such1′1-thiocarbonyldi-2(1H)-pyridone (J. Org. Chem. 1986, 51, 2613) or1,1′-thiocarbonyl diimidazole, typically1′1-thiocarbonyldi-2(1H)-pyridone, and a suitable base such astriethylamine, pyridine or Hünig's base, in a suitable solvent such asdichloromethane or tetrahydrofuran, under ambient conditions for 18 to24 hours. Typical conditions comprise of

-   -   a) reacting 1 equivalent of suitable aminopyridine and 1        equivalent of 1′1-thiocarbonyldi-2(1H)-pyridone in        dichloromethane at 0 to 25° C. for 1 hour, then    -   b) adding 1 equivalent of compound (II) and 1 equivalent of        triethylamine in dichloromethane and stirring under ambient        conditions for 18 hours.

Alternatively, process step (i) may involve the formation of a urea bycoupling of compound (II) with a suitable aminopyridine, in the presenceof a suitable carbonyl transfer agent such as N,N′-carbonyldiimidazole,followed by subsequent sulfonation using a suitable sulfonating agentsuch as Lawesson's reagent.

In a further embodiment compounds of general formula (III) can beprepared as described in Scheme 2.

Compounds of general formula (IV) can be prepared from compounds ofgeneral formula (III) by process step (ii) which comprises methylationof the thiourea (III) using a suitable methylating agent such as methyliodide or methyl p-toluenesulfonate, in the presence of a suitable basesuch as potassium tert-butoxide in a suitable solvent such astetrahydrofuran or diethyl ether, between 0° C. and the refluxtemperature of the solvent for about 18 hrs. Typical conditions comprisereacting 1 equivalent of compound (III), 1 to 1.2 equivalents potassiumtert-butoxide, 1 to 1.2 equivalents methyl p-toluenesulfonate, intetrahydrofuran, under ambient conditions for 1 to 18 hrs.

Compounds of general formula (V) can be prepared from compounds ofgeneral formula (IV) by process step (iii) which comprises reaction ofcompounds of general formula (IV) with a suitable hydrazideR²R³CHCONHNH₂, optionally in the presence of a suitable acid catalystsuch as trifluoroacetic acid or para-toluenesulfonic acid, in a suitablesolvent such as tetrahydrofuran or n-butanol, at a temperature betweenroom temperature and the reflux temperature of the solvent. Typicalconditions comprise reacting 1 equivalent of compound (IV), an excess ofhydrazide R²R³CHCONHNH₂ and trifluoroacetic acid (catalytic amount) intetrahydrofuran, heated under reflux for 1 to 18 hours.

Alternatively, compounds of formula (V) may be prepared from compoundsof formula (III) using process steps (ii) and (iii) as a one-potsynthesis.

Compounds of formula (VI) are commercially available or known in theliterature.

Compounds of general formula (I) can be prepared from compounds ofgeneral formula (V) and (VI) by process step (iv) wherein compound (VI)is treated with a suitable strong base such sodium hydride or potassiumtert-butoxide followed by reaction with compound (V), in a suitablesolvent such as N,N-dimethylformamide or dimethylsulfoxide, at atemperature between room temperature and the reflux temperature of thesolvent, for 18 to 40 hours. Typical conditions comprise reacting 2equivalents of compound (VI), 2 equivalents of sodium hydride, and 1equivalent of compound (V), in N,N-dimethylformamide, heated at 100° C.for up to 40 hours.

Compounds of formula (VII) can be prepared as described in J. Org. Chem.(1980), 45, 4219. Compounds of formula (II) can be prepared as describedin WO 97/25322 at p 64.

Compounds of formula (III) can be prepared from compounds of formula(II) and (VII) by process step (v) wherein compounds (VII) and (II) arereacted together, optionally in the presence of a suitable base such astriethylamine, pyridine or Hünig's base, in a suitable solvent such asdichloromethane or tetrahydrofuran, under ambient conditions for 2 to 24hours. Typical conditions comprise reacting 1 equivalent of compound(VI) and 1 equivalent of compound (II) in dichloromethane, under ambientconditions for 2 to 24 hours.

Alternatively compounds of formula (I) can also be prepared as describedin Scheme 3.

Y represents O or N(C₁-C₆)alkyl.

Z represent a suitable functional group such as OH or halogen. When Y=O,Z is typically OH; when Y=N(C₁-C₆)alkyl, Z is typically halogen, inparticular chloro or bromo.

PG represents a suitable protecting group. When Y=O, PG is typicallyacyl or benzyl.

When Y=N(C₁-C₆)alkyl, PG is typically Boc or CBz.

PG′ represents a suitable amine protecting group such as benzyl or Boc

Compounds of formula (VIII) can be prepared by analogy with the methodsused by M. G. Banwell (J. Org. Chem. 2003, 68, 613).

Compounds of general formula (IX) can be prepared from compounds ofgeneral formula (VIII) by process step (vi) which comprises deprotectionof the amino group using standard methodology as described in“Protecting Groups in Organic Synthesis” by T. W. Greene and P. Wutz.Typical conditions comprise reacting 1 equivalent of compound (VIII) inthe presence of a suitable catalyst, such as 10% Pd/C, in a suitablesolvent, such as ethanol/water (90:10) or tetrahydrofuran, under 60 psiof hydrogen at room temperature for 2 to 18 hours.

Compounds of general formula (X) can be prepared from compounds ofgeneral formula (IX) by process step (i) as described in Scheme 1.

Alternatively, compounds of formula (X) can be prepared from compoundsof formula (IX) and (VII) by process step (v), as described in Scheme 2.

Compounds of general formula (XI) can be prepared from compounds ofgeneral formula (X) by process step (ii) as described in Scheme 1.

Compounds of general formula (XII) can be prepared from compounds ofgeneral formula (XI) by process step (iii) as described in Scheme 1.

Compounds of formula (XIII) may be prepared from compounds of generalformula (XII) by process step (vii) which comprises deprotection of Yusing standard methodology as described in “Protecting Groups in OrganicSynthesis” by T. W. Greene and P. Wutz.

When PG=acyl, typical conditions comprise reacting 1 equivalent ofcompound (XI) and 2.5 to 3 equivalents of potassium carbonate indichloromethane under ambient conditions for 18 hours.

When PG=benzyl, typical conditions comprise reacting 1 equivalent ofcompound (XI) in the presence of a suitable catalyst, such as 10% Pd/C,in a suitable solvent, such as ethanol/water (90:10) or tetrahydrofuran,under 60 psi of hydrogen at room temperature for 2 to 18 hours.

Compounds of formula (I) can be prepared from compounds of generalformula (XIII) and R¹Z (XIV) by process step (viii).

When Z=OH compounds of formula (I) can be obtained by a suitablereaction, typically a Mitsunobu reaction, between compounds (XIII) and(XIV) in the presence of a suitable phosphine, such as tri-n-butylphosphine or triphenyl phosphine, and a suitable azo compound, such asdiisopropylazodicarboxylate or di-tert-butyl azodicarboxylate, in asolvent such as dichloromethane, tetrahydrofuran orN,N-dimethylformamide, at temperatures between 25 to 115° C., for 1 to48 hours. Typical conditions comprise reacting 1 equivalent of compound(I), 2 equivalents of compound (XIV), 3 equivalents oftriphenylphosphine and 2 equivalents of di-tert-butyl azodicarboxylate,in dichloromethane, at 25° C. for 4 hours.

When X═N(C₁-C₆)alkyl and Z=halogen (e.g. Cl), compounds of formula (I)can be obtained by a suitable reaction, typically a N-alkylation,between compounds (XIII) and (XIV), in the presence of a suitable basesuch as N,N-diisopropylethylamine or triethylamine, in a suitablesolvent such as N,N-dimethylformamide or dimethylsulfoxide, at elevatedtemperature for 1 to 18 hours. Typical conditions comprise reacting 1equivalent of compound (XIII), 1 to 1.2 equivalents of compound (XIV)and 1 to 2 equivalents of N,N-diisopropylethylamine, indimethylsulfoxide at elevated temperature for 16 hours.

Compounds of formula (I) can alternatively be prepared as described inScheme 4.

Y represents O or N(C₁-C₆)alkyl.

PG″ represents a suitable amine protecting group, typically benzyl.

When Y=O, compounds of general formula (XV) are commercially available.

When Y=N(C₁-C₆)alkyl, compounds of formula (XV) can be prepared asdescribed in WO 03/089412 at page 22.

Compounds of general formula (XVI) may be prepared from compounds offormula (XV) and (VI) by process step (viii) as described in Scheme 3.

Compounds of general formula (XVII) may be prepared from compounds offormula (XVI) by process step (vi) as described in Scheme 3.

Compounds of general formula (XVIII) may be prepared from compounds offormula (XVII) by process step (i) as described in Scheme 1.

Alternatively, compounds of formula (XVIII) can be prepared fromcompounds of formula (XVII) and (VII) by process step (v), as describedin Scheme 2.

Compounds of general formula (XIX) may be prepared from compounds offormula (XVIII) by process step (ii) as described in Scheme 1.

Compounds of general formula (I) may be prepared from compounds offormula (XIX) by process step (iii) as described in Scheme 1.

Alternatively, compounds of general formula (I) may be prepared fromcompounds of formula (XVIII) by combination of process steps (ii) and(iii), in a one-pot synthesis, as described in Scheme 1.

In a further embodiment, where X═O and m, n, and R¹ to R⁸ are asdescribed herein, compounds of formula (I) can be prepared as describedin Scheme 5.

PG′″ is a suitable protecting amine group, typically diphenylmethyl.

Compounds of formula (XX) are commercially available.

Compounds of formula (XXI) may be prepared from compounds of formula(XX) by process step (ix) which comprises reaction of ketone (XX) withan “activated” alkyl (organometallic alkyl such as R⁸Mgl, R⁸MgCl orR⁸Li) to give the corresponding tertiary alcohol of formula (XXI).Typical conditions comprise reacting 1 equivalent of compound (XX) and 2to 2.5 equivalents of R⁸Mgl in a suitable solvent such astetrahydrofuran or diethyl ether, at 0 to 25° C. for 1 to 8 hours.

Compounds of formula (XXII) may be prepared from compounds of formula(XXI) and (VI) by process step (viii) as described in Scheme 3.

Compounds of formula (XXIII) may be prepared from compounds of formula(XXII) by process step (vi) as described in Scheme 3.

Compounds of formula (XXIV) may be prepared from compounds of formula(XXIII) by process step (i) as described in Scheme 1.

Compounds of formula (XXV) may be prepared from compounds of formula(XXIV) by process step (ii) as described in Scheme 1.

Compounds of formula (I) may be prepared from compounds of formula (XXV)by process step (iii) as described in Scheme 1.

Alternatively, Scheme 6 provides a route to the preparation of compoundsof formula (I).

Compounds of formula (XXVI) may be prepared as described in WO 04/062665at p 46.

Compounds of formula (XXVII) may be prepared from compounds of formula(XXVI) by process step (x) which comprises treatment of compound (XXVI)with a suitable thiocarbonyl transfer agent thiourea such1′1-thiocarbonyldi-2(1H)-pyridone (J. Org. Chem. 1986, 51, 2613), in asuitable solvent such as dichloromethane or tetrahydrofuran, underambient conditions for 1 to 18 hours. Typical conditions comprisereacting 1.0 equivalent of compound (XXVI) and 1.0 equivalent of1′1-thiocarbonyldi-2(1H)-pyridone in dichloromethane at room temperaturefor 18 hours.

Compounds of formula (XXVIII) can be prepared from compounds of generalformula (XXVII) by process step (i) as described in Scheme 1.

Compounds of formula (XXIX) can be prepared from compounds of generalformula (XXVIII) by process step (ii) as described in Scheme 1.

Compounds of formula (XXX) can be prepared from compounds of generalformula (XXIX) by process step (ii) as described in Scheme 1.

Compounds of formula (I) can be prepared from compounds of generalformula (XXX) and (VI) by process step (iv) as described in Scheme 1.

All of the above reactions and the preparations of novel startingmaterials disclosed in the preceding methods are conventional andappropriate reagents and reaction conditions for their performance orpreparation as well as procedures for isolating the desired productswill be well known to those skilled in the art with reference toliterature precedents and the examples and preparations hereto.

The compounds of the invention are useful because they havepharmacological activity in mammals, including humans. Moreparticularly, they are useful in the treatment or prevention of adisorder in which modulation of the levels of oxytocin could provide abeneficial effect. Disease states that may be mentioned include sexualdysfunction, particularly premature ejaculation, preterm labour,complications in labour, appetite and feeding disorders, benignprostatic hyperplasia, premature birth, dysmenorrhoea, congestive heartfailure, arterial hypertension, liver cirrhosis, nephrotic hypertension,occular hypertension, obsessive compulsive disorder and neuropsychiatricdisorders.

Sexual dysfunction (SD) is a significant clinical problem which canaffect both males and females. The causes of SD may be both organic aswell as psychological. Organic aspects of SD are typically caused byunderlying vascular diseases, such as those associated with hypertensionor diabetes mellitus, by prescription medication and/or by psychiatricdisease such as depression. Physiological factors include fear,performance anxiety and interpersonal conflict. SD impairs sexualperformance, diminishes self-esteem and disrupts personal relationshipsthereby inducing personal distress. In the clinic, SD disorders havebeen divided into female sexual dysfunction (FSD) disorders and malesexual dysfunction (MSD) disorders (Melman et al, J. Urology, 1999, 161,5-11).

FSD can be defined as the difficulty or inability of a woman to findsatisfaction in sexual expression. FSD is a collective term for severaldiverse female sexual disorders (Leiblum, S. R. (1998). Definition andclassification of female sexual disorders. Int. J. Impotence Res., 10,S104-S106; Berman, J. R., Berman, L. & Goldstein, I. (1999). Femalesexual dysfunction: Incidence, pathophysiology, evaluations andtreatment options. Urology, 54, 385-391). The woman may have lack ofdesire, difficulty with arousal or orgasm, pain with intercourse or acombination of these problems. Several types of disease, medications,injuries or psychological problems can cause FSD. Treatments indevelopment are targeted to treat specific subtypes of FSD,predominantly desire and arousal disorders.

The categories of FSD are best defined by contrasting them to the phasesof normal female sexual response: desire, arousal and orgasm (Leiblum,S. R. (1998). Definition and classification of female sexual disorders,Int. J. Impotence Res., 10, S104-S106). Desire or libido is the drivefor sexual expression. Its manifestations often include sexual thoughtseither when in the company of an interested partner or when exposed toother erotic stimuli. Arousal is the vascular response to sexualstimulation, an important component of which is genital engorgement andincludes increased vaginal lubrication, elongation of the vagina andincreased genital sensation/sensitivity. Orgasm is the release of sexualtension that has culminated during arousal.

Hence, FSD occurs when a woman has an inadequate or unsatisfactoryresponse in any of these phases, usually desire, arousal or orgasm. FSDcategories include hypoactive sexual desire disorder, sexual arousaldisorder, orgasmic disorders and sexual pain disorders. Although thecompounds of the invention will improve the genital response to sexualstimulation (as in female sexual arousal disorder), in doing so it mayalso improve the associated pain, distress and discomfort associatedwith intercourse and so treat other female sexual disorders.

Thus, in accordance with a further aspect of the invention, there isprovided the use of a compound of the invention in the preparation of amedicament for the treatment or prophylaxis of hypoactive sexual desiredisorder, sexual arousal disorder, orgasmic disorder and sexual paindisorder, more preferably for the treatment or prophylaxis of sexualarousal disorder, orgasmic disorder, and sexual pain disorder, and mostpreferably in the treatment or prophylaxis of sexual arousal disorder.

Hypoactive sexual desire disorder is present if a woman has no or littledesire to be sexual, and has no or few sexual thoughts or fantasies.This type of FSD can be caused by low testosterone levels, due either tonatural menopause or to surgical menopause. Other causes includeillness, medications, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterised by inadequategenital response to sexual stimulation. The genitalia do not undergo theengorgement that characterises normal sexual arousal. The vaginal wallsare poorly lubricated, so that intercourse is painful. Orgasms may beimpeded. Arousal disorder can be caused by reduced oestrogen atmenopause or after childbirth and during lactation, as well as byillnesses, with vascular components such as diabetes andatherosclerosis. Other causes result from treatment with diuretics,antihistamines, antidepressants eg SSRIs or antihypertensive agents.

Sexual pain disorders (includes dyspareunia and vaginismus) ischaracterised by pain resulting from penetration and may be caused bymedications which reduce lubrication, endometriosis, pelvic inflammatorydisease, inflammatory bowel disease or urinary tract problems.

The prevalence of FSD is difficult to gauge because the term coversseveral types of problem, some of which are difficult to measure, andbecause the interest in treating FSD is relatively recent. Many women'ssexual problems are associated either directly with the female ageingprocess or with chronic illnesses such as diabetes and hypertension.

Because FSD consists of several subtypes that express symptoms inseparate phases of the sexual response cycle, there is not a singletherapy. Current treatment of FSD focuses principally on psychologicalor relationship issues. Treatment of FSD is gradually evolving as moreclinical and basic science studies are dedicated to the investigation ofthis medical problem. Female sexual complaints are not all psychologicalin pathophysiology, especially for those individuals who may have acomponent of vasculogenic dysfunction (eg FSAD) contributing to theoverall female sexual complaint. There are at present no drugs licensedfor the treatment of FSD. Empirical drug therapy includes oestrogenadministration (topically or as hormone replacement therapy), androgensor mood-altering drugs such as buspirone or trazodone. These treatmentoptions are often unsatisfactory due to low efficacy or unacceptableside effects.

The Diagnostic and Statistical Manual (DSM) IV of the AmericanPsychiatric Association defines Female Sexual Arousal Disorder (FSAD) asbeing:

-   -   “a persistent or recurrent inability to attain or to maintain        until completion of the sexual activity adequate        lubrication-swelling response of sexual excitement. The        disturbance must cause marked distress or interpersonal        difficulty.”

The arousal response consists of vasocongestion in the pelvis, vaginallubrication and expansion and swelling of the external genitalia. Thedisturbance causes marked distress and/or interpersonal difficulty.

FSAD is a highly prevalent sexual disorder affecting pre-, peri- andpost menopausal (±HRT) women. It is associated with concomitantdisorders such as depression, cardiovascular diseases, diabetes and UGdisorders.

The primary consequences of FSAD are lack of engorgement/swelling, lackof lubrication and lack of pleasurable genital sensation. The secondaryconsequences of FSAD are reduced sexual desire, pain during intercourseand difficulty in achieving an orgasm.

Male sexual dysfunction (MSD) is generally associated with eithererectile dysfunction, also known as male erectile dysfunction (MED)and/or ejaculatory disorders such as premature ejaculation, anorgasmia(unable to achieve orgasm) or desire disorders such as hypoactive sexualdesire disorder (lack of interest in sex).

PE is a relatively common sexual dysfunction in men. It has been definedin several different ways but the most widely accepted is the Diagnosticand Statistical Manual of Mental Disorders IV one which states:

-   -   “PE is a lifelong persistent or recurrent ejaculation with        minimal sexual stimulation before, upon or shortly after        penetration and before the patient wishes it. The clinician must        take into account factors that affect duration of the excitement        phase, such as age, novelty of the sexual partner or        stimulation, and frequency of sexual activity. The disturbance        causes marked distress of interpersonal difficulty.”        The International Classification of Diseases 10 definition        states:    -   “There is an inability to delay ejaculation sufficiently to        enjoy lovemaking, manifest as either of the following: (1)        occurrence of ejaculation before or very soon after the        beginning of intercourse (if a time limit is required: before or        within seconds of the beginning of intercourse); (2) ejaculation        occurs in the absence of sufficient erection to make intercourse        possible. The problem is not the result of prolonged abstinence        from sexual activity”        Other definitions which have been used include classification on        the following criteria:

Related to partner's orgasm

Duration between penetration and ejaculation

Number of thrust and capacity for voluntary control

Psychological factors may be involved in PE, with relationship problems,anxiety, depression, prior sexual failure all playing a role.

Ejaculation is dependent on the sympathetic and parasympathetic nervoussystems. Efferent impulses via the sympathetic nervous system to the vasdeferens and the epididymis produce smooth muscle contraction, movingsperm into the posterior urethra. Similar contractions of the seminalvesicles, prostatic glands and the bulbouretheral glands increase thevolume and fluid content of semen. Expulsion of semen is mediated byefferent impulses originating from a population of lumber spinothalamiccells in the lumbosacral spinal cord (Coolen & Truitt, Science, 2002,297, 1566) which pass via the parasympathetic nervous system and causerhythmic contractions of the bulbocavernous, ischiocavernous and pelvicfloor muscles. Cortical control of ejaculation is still under debate inhumans. In the rat the medial pre-optic area and the paraventricularnucleus of the hypothalamus seem to be involved in ejaculation.

Ejaculation comprises two separate components—emission and ejaculation.Emission is the deposition of seminal fluid and sperm from the distalepididymis, vas deferens, seminal vesicles and prostrate into theprostatic urethra. Subsequent to this deposition is the forcibleexpulsion of the seminal contents from the urethral meatus. Ejaculationis distinct from orgasm, which is purely a cerebral event. Often the twoprocesses are coincidental.

A pulse of oxytocin in peripheral serum accompanies ejaculation inmammals. In man oxytocin but not vasopressin plasma concentrations aresignificantly raised at or around ejaculation. Oxytocin does not induceejaculation itself; this process is 100% under nervous control viaα1-adrenoceptor/sympathetic nerves originating from the lumbar region ofthe spinal cord. The systemic pulse of oxytocin may have a role in theperipheral ejaculatory response. It could serve to modulate thecontraction of ducts and glandular lobules throughout the male genitaltract, thus influencing the fluid volume of different ejaculatecomponents for example. Oxytocin released centrally into the brain couldinfluence sexual behaviour, subjective appreciation of arousal (orgasm)and latency to subsequent ejaculation.

Accordingly, one aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention or treatment of sexual dysfunction,preferably male sexual dysfunction, most preferably prematureejaculation. It has been demonstrated in the scientific literature thatthe number of oxytocin receptors in the uterus increases duringpregnancy, most markedly before the onset of labour (Gimpl & Fahrenholz,2001, Physiological Reviews, 81 (2), 629-683.). Without being bound byany theory it is known that the inhibition of oxytocin can assist inpreventing preterm labour and in resolving complications in labour.

Accordingly, another aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention or treatment of preterm labour andcomplications in labour.

Oxytocin has a role in feeding; it reduces the desire to eat (Arletti etal., Peptides, 1989, 10, 89). By inhibiting oxytocin it is possible toincrease the desire to eat. Accordingly oxytocin inhibitors are usefulin treating appetite and feeding disorders.

Accordingly, a further aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention or treatment of appetite and feedingdisorders.

Oxytocin is implicated as one of the causes of benign prostatichyperplasia (BPH). Analysis of prostate tissue have shown that patientswith BPH have increased levels of oxytocin (Nicholson & Jenkin, Adv.Exp. Med. & Biol., 1995, 395, 529). Oxytocin antagonists can help treatthis condition.

Accordingly, another aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention or treatment of benign prostatichyperplasia.

Oxytocin has a role in the causes of dysmenorrhoea due to its activityas a uterine vasoconstrictor (Akerlund, Ann. NY Acad. Sci., 1994, 734,47). Oxytocin antagonists can have a therapeutic effect on thiscondition.

Accordingly, a further aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention of treatment of dysmenorrhoea.

It is to be appreciated that all references herein to treatment includecurative, palliative and prophylactic treatment.

The compounds of the present invention may be co-administered with oneor more agents selected from:

-   1) One or more selective serotonin reuptake inhibitors (SSRIs) such    as dapoxetine, paroxetine,    3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzenesulfonamide    (Example 28, WO 0172687),    3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzenesulfonamide    (Example 12, WO 0218333),    N-methyl-N-({3-[3-methyl-4-(methylsulfanyl)phenoxy]-4-pyridinyl}methyl)amine    (Example 38, PCT Application no PCT/IB02/01032).-   2) One or more local anaesthetics;-   3) one or more α-adrenergic receptor antagonists (also known as    α-adrenoceptor blockers, α-receptor blockers or α-blockers);    suitable α₁-adrenergic receptor antagonists include: phentolamine,    prazosin, phentolamine mesylate, trazodone, alfuzosin, indoramin,    naftopidil, tamsulosin, phenoxybenzamine, rauwolfa alkaloids,    Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591,    doxazosin, Example 19 of WO9830560, terazosin and abanoquil;    suitable α₂-adrenergic receptor antagonists include dibenarnine,    tolazoline, trimazosin, efaroxan, yohimbine, idazoxan clonidine and    dibenarnine; suitable non-selective α-adrenergic receptor    antagonists include dapiprazole; further α-adrenergic receptor    antagonists are described in PCT application WO99/30697 published on    14 Jun. 1998 and U.S. Pat. Nos. 4,188,390; 4,026,894; 3,511,836;    4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009;    4,252,721 and 2,599,000 each of which is incorporated herein by    reference;-   4) one or more cholesterol lowering agents such as statins (e.g.    Atorvastatin/Lipitor™) and fibrates;-   5) one or more of a serotonin receptor agonist, antagonist or    modulator, more particularly agonists, antagonists or modulators for    example 5HT1A, 5HT2A, 5HT2C, 5HT3, 5HT6 and/or 5HT7 receptors,    including those described in WO-09902159, WO-00002550 and/or    WO-00028993;-   6) one or more NEP inhibitors, preferably wherein said NEP is EC    3.4.24.11 and more preferably wherein said NEP inhibitor is a    selective inhibitor for EC 3.4.24.11, more preferably a selective    NEP inhibitor is a selective inhibitor for EC 3.4.24.11, which has    an IC₅₀ of less than 100 nM (e.g. ompatrilat, sampatrilat) suitable    NEP inhibitor compounds are described in EP-A-1097719; IC50 values    against NEP and ACE may be determined using methods described in    published patent application EP1097719-A1, paragraphs [0368] to    [0376];-   7) one or more of an antagonist or modulator for vasopressin    receptors, such as relcovaptan (SR 49059), conivaptan, atosiban,    VPA-985, CL-385004, Vasotocin.-   8) Apomorphine—teachings on the use of apomorphine as a    pharmaceutical may be found in U.S. Pat. No. 5,945,117;-   9) Dopamine agonists (in particular selective D2, selective D3,    selective D4 and selective D2-like agents) such as Pramipexole    (Pharmacia Upjohn compound number PNU95666), ropinirole,    apomorphine, surmanirole, quinelorane, PNU-142774, bromocriptine,    carbergoline, Lisuride;-   10) Melanocortin receptor agonists (e.g. Melanotan II and PT141) and    selective MC3 and MC4 agonists (e.g. THIQ);-   11) Mono amine transport inhibitors, such as Noradrenaline    (norepinephrine) re-uptake inhibitors (NRIs), especially selective    NRIs such as reboxetine, either in its racemic (R,R/S,S) or    optically pure (S,S) enantiomeric form, particularly    (S,S)-reboxetine, other Serotonin Re-uptake Inhibitors (SRIs) (e.g.    paroxetine, dapoxetine) or Dopamine Re-uptake Inhibitors (DRIs);-   12) 5-HT_(1A) antagonists (e.g. robalzotan); and-   13) PDE inhibitors such as PDE2 (e.g.    erythro-9-(2-hydroxyl-3-nonyl)-adenine) and Example 100 of EP    0771799-incorporated herein by reference) and in particular a PDE5    inhibitor such as the pyrazolo[4,3-d]pyrimidin-7-ones disclosed in    EP-A-0463756; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in    EP-A-0526004; the pyrazolo[4,3-d]pyrimidin-7-ones disclosed in    published international patent application WO 93/06104; the isomeric    pyrazolo[3,4-d]pyrimidin-4-ones disclosed in published international    patent application WO 93/07149; the quinazolin-4-ones disclosed in    published international patent application WO 93/12095; the    pyrido[3,2-d]pyrimidin-4-ones disclosed in published international    patent application WO 94/05661; the purin-6-ones disclosed in    published international patent application WO 94/00453; the    pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published international    patent application WO 98/49166; the pyrazolo[4,3-d]pyrimidin-7-ones    disclosed in published international patent application WO 99/54333;    the pyrazolo[4,3-d]pyrimidin-4-ones disclosed in EP-A-0995751; the    pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published international    patent application WO 00/24745; the pyrazolo[4,3-d]pyrimidin-4-ones    disclosed in EP-A-0995750; the compounds disclosed in published    international application WO95/19978; the compounds disclosed in    published international application WO 99/24433 and the compounds    disclosed in published international application WO 93/07124; the    pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published international    application WO 01/27112; the pyrazolo[4,3-d]pyrimidin-7-ones    disclosed in published international application WO 01/27113; the    compounds disclosed in EP-A-1092718 and the compounds disclosed in    EP-A-1092719.    Preferred PDE5 inhibitors for use with the invention:-   5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (sildenafil) also known as    1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine    (see EP-A-0463756);-   5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see EP-A-0526004);-   3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO98/49166);-   3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxyl)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO99/54333);-   (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1    (R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    also known as    3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO99/54333);-   5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    also known as    1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine    (see WO 01/27113, Example 8);-   5-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO 01/27113, Example 15);-   5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO 01/27113, Example 66);-   5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO 01/27112, Example 124);-   5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO 01/27112, Example 132);-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)    pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione (IC-351), i.e. the    compound of examples 78 and 95 of published international    application WO95/19978, as well as the compound of examples 1, 3, 7    and 8;-   2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one    (vardenafil) also known as    1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine,    i.e. the compound of examples 20, 19, 337 and 336 of published    international application WO99/24433; and-   the compound of example 11 of published international application    WO93/07124 (EISAI); and-   compounds 3 and 14 from Rotella D P, J. Med. Chem., 2000, 43, 1257.    Still further PDE5 inhibitors for use with the invention include:    -   4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone;        1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinozolinyl]-4-piperidine-carboxylic        acid, monosodium salt;        (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one;        furazlocillin;        cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]purin-4-one;        3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;        3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;        4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)        propoxy)-3-(2H)pyridazinone;        I-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;        1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic        acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome);        Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa        Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering        Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai);        Bay-38-3045 & 38-9456 (Bayer) and Sch-51866.

The contents of the published patent applications and journal articlesand in particular the general formulae of the therapeutically activecompounds of the claims and exemplified compounds therein areincorporated herein in their entirety by reference thereto.

More preferred PDE5 inhibitors for use with the invention are selectedfrom the group:

-   5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (sildenafil);-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)    pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione (IC-351);-   2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one    (vardenafil); and-   5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    or    5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    and pharmaceutically acceptable salts thereof.

A particularly preferred PDE5 inhibitor is5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil) (also known as1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine)and pharmaceutically acceptable salts thereof. Sildenafil citrate is apreferred salt.

Preferred agents for coadministration with the compounds of the presentinvention are PDE5 inhibitors, selective serotonin reuptake inhibitors(SSRIs), vasopressin V_(1A) antagonists, α-adrenergic receptorantagonists, NEP inhibitors, dopamine agonists and melanocortin receptoragonists as described above. Particularly preferred agents forcoadministration are PDE5 inhibitors, SSRIs, and V_(1A) antagonists asdescribed herein.

The compounds of the formula (I) can be administered alone but willgenerally be administered in admixture with a suitable pharmaceuticalexcipient, diluent or carrier selected with regard to the intended routeof administration and standard pharmaceutical practice.

The present invention provides for a composition comprising a compoundof formula (I) and a pharmaceutically acceptable diluent or carrier.

A suitable assay for determining the oxytocin antagonist activity of acompound is detailed herein below.

Oxytocin Receptor Beta-Lactamase Assay

Materials

Cell culture/Reagents

A: cell culture

Nutrient Mixture

F12 Ham's

Foetal Bovine Serum (FBS)

Geneticin

Zeocin

Trypsin/EDTA

PBS (phosphate buffered saline)

HEPES

B: reagents

Oxytocin

OT receptor-specific antagonist

Molecular grade Dimethyl Sulphoxide (DMSO)

Trypan Blue Solution 0.4%

CCF4-AM (Solution A)

Pluronic F127s (Solution B)

24% PEG, 18% TR40 (Solution C)

Probenecid (Dissolved at 200 mM in 200 mM NaOH, Solution D) Methods:

Cell Culture: Cells used are CHO-OTR/NFAT-β-Lactamase. TheNFAT-β-lactamase expression construct was transfected into the CHO-OTRcell line and clonal populations were isolated via fluorescenceactivated cell sorting (FACS). An appropriate clone was selected todevelop the assay.

Growth Medium

90% F12 Nutrient Mix, 15 mM HEPES

10% FBS

400 μg/ml Geneticin

200 μg/ml Zeocin

2 mM L-Glutamine

Assay Media

99.5% F12 Nutrient Mix, 15 mM HEPES

0.5% FBS

Recovery of cells—A vial of frozen cells is thawed rapidly in 37° C.water bath and the cell suspension transferred into a T225 flask with 50ml of fresh growth medium and then incubated at 37° C., 5% CO₂ in anincubator until the cells adhered to the flask Replace media with 50 mlof fresh growth media the following day.

Culturing cells—CHO-OTR-NFAT-βLactamase cells were grown in growthmedium. Cells were harvested when they reached 80-90% confluenceremoving the medium and washing with pre-warmed PBS. PBS was thenremoved and Trypsin/EDTA added (3 mls for T225 cm² flask) beforeincubating for 5 min in 37° C./5% CO₂ incubator. When cells weredetached, pre-warmed growth media was added (7 mls for T225 cm² flask)and the cells re-suspended and mixed gently by pipetting to achievesingle cell suspension. The cells were split into T225 flask at 1:10(for 3 days growth) and 1:30 (for 5 days growth) ratio in 35 ml growthmedium.

β-Lactamase Assay Method

Day 1: Cell Plate Preparation

Cells grown at 80-90% confluence were harvested and counted. Suspensionsof cells at 2×105 cells/ml in growth medium were prepared and 30 μl ofcells suspension added in 384-well, black clear-bottom plates. A blankplate containing diluents from each reagent was used for backgroundsubtraction.

Plates were incubated at 37° C., 5% CO₂ overnight.

Day 2: Cells Stimulation

-   -   10 μl antagonist/compound (diluted in assay media containing        1.25% DMSO=antagonist diluent) was added to appropriate wells        and incubated for 15 minutes at 37° C., 5% CO₂.    -   10 μl oxytocin, made up in assay media, was added to all wells        and incubated for 4 hours at 37° C., 5% CO₂.    -   A separate 384-well cell plate was used to generate an oxytocin        dose response curve. (10 μl antagonist diluent was added to        every well. 10 μl of oxytocin was then added. The cells are then        treated as per antagonist/compound cell plates).

Preparation of 1 ml of 6× Loading Buffer with Enhanced Loading Protocol(this requires scale-up according to number of plates to be screened).

-   -   12 μl of solution A (1 mM CCF4-AM in Dry DMSO) was added to 60        μl of solution B (100 mg/ml Pluronic-F127 in DMSO+0.1% Acetic        Acid) and vortexed.    -   The resulting solution was added to 925 μl of solution C (24%        w/w PEG400, 18% TR40 v/v in water).    -   75 μl of solution D was added (200 mM probenecid in 200 mM        NaOH).    -   10 μl of 6× Loading Buffer was added to all wells and incubated        for 1.5 hrs-2 hrs at room temperature in the dark.    -   The plates were read using an LJL Analyst, Excitation 405 nm,        Emission 450 nm and 530 nm, gain optimal, lagtime 0.40 μs        integration, 4 flashes, bottom reading.

Using the assay described above, the compounds of the present inventionall exhibit oxytocin antagonist activity, expressed as a Ki value, ofless than 1 μM. Preferred examples have Ki values of less than 200 nMand particularly preferred examples have Ki values of less than 50 nM.The compound of Example 48 has a Ki value of 1.8 nM. The compound ofExample 43 has a Ki value of 4.2 nM. The compound of Example 25 has a Kivalue of 9 nM. The compound of Example 28 has a Ki value of 13.8 nM.

The invention is illustrated by the following non-limiting examples inwhich the following abbreviations and definitions are used:

-   -   Arbocel® Filtration agent, from J. Rettenmaier & Sohne, Germany    -   APCI+ Atmospheric Pressure Chemical Ionisation (positive scan)    -   CDCl₃ Chloroform-d1    -   d Doublet    -   dd Doublet of doublets    -   DMSO Dimethylsulfoxide    -   ES+ Electrospray ionisation positive scan.    -   eq Equivalent    -   ¹H NMR Proton Nuclear Magnetic Resonance Spectroscopy    -   HRMS High resolution mass spectrum    -   LCMS Liquid chromatography-mass spectroscopy    -   LRMS Low resolution mass spectrum    -   MS (Low Resolution) Mass Spectroscopy    -   m Multiplet    -   PXRD Powder X-Ray Diffraction    -   m/z Mass spectrum peak    -   q Quartet    -   s Singlet    -   t Triplet    -   δ Chemical shift

Preparation 1 Azetidin-3-yl methanesulfonate hydrochloride

A mixture of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (WO97/25322, p 64), (20 g, 63 mmol) and chloroethylchloroformate (10 mL, 95mmol) in dichloromethane (100 mL) was heated under reflux for 2.5 hours.The reaction mixture was then concentrated in vacuo and the residue wasre-dissolved in methanol (100 mL) and heated under reflux for a further2.5 hours. The mixture was then cooled to room temperature andconcentrated in vacuo to afford the title compound as a white solid inquantitative yield, 9.6 g. ¹H NMR (400 MHz, DMSO-d₆) δ: 3.28 (s, 3H),4.06 (m, 2H), 4.31 (m, 2H), 5.34 (m, 1H)

Preparation 21-{[(6-Methoxypyridin-3-yl)amino]carbonothioyl}azetidin-3-ylmethanesulfonate

A solution of 5-amino-2-methoxypyridine (6.4 g, 51.5 mmol) indichloromethane (20 mL) was added to an ice-cooled solution of1′1-thiocarbonyldi-2(1H)-pyridone (12.05 g, 51.5 mmol) indichloromethane (100 mL) and the mixture was stirred for 1 hour. Theproduct of preparation 1 (9.6 g, 51.5 mmol) and triethylamine (7.24 mL,51.5 mmol) were then added and the mixture was stirred for 18 hours. Thereaction mixture was then filtered and the filtrate was washed with 10%citric acid, sodium hydrogen carbonate solution and brine. The organicsolution was dried over magnesium sulfate, concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 100:0 to 95:5, to afford the titlecompound as a pink solid in 29% yield, 4.7 g. ¹H NMR (400 MHz, DMSO-d₆)δ: 2.48 (s, 3H), 3.82 (s, 3H), 4.17 (m, 2H), 4.48 (m, 2H), 5.35 (m, 1H),6.78 (d, 1H), 7.73 (dd, 1H), 8.08 (d, 1H); LRMS APCI m/z 318 [M+H]⁺.

Preparation 3 MethylN-(6-methoxypyridin-3-yl)-3-[(methylsulfonyl)oxy]azetidine-1-carbimidothioate

Potassium tert-butoxide (1.8 g, 16.3 mmol) was added to a solution ofthe product of preparation 2 (4.3 g, 13.6 mmol) in tetrahydrofuran (100mL) and the mixture was stirred at room temperature for 30 minutes.Methyl p-toluenesulfonate (3.63 g, 16.3 mmol) was then added and themixture was stirred for 18 hours at room temperature. The reactionmixture was then diluted with water and brine and extracted with diethylether (2×50 mL). The combined organic solution was then dried overmagnesium sulfate, concentrated in vacuo, and the residue was purifiedby column chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 95:5, to afford the title compoundthe title compound as a red oil in 82% yield, 3.76 g. ¹H NMR (400 MHz,CDCl₃) δ: 2.20 (s, 3H), 3.05 (s, 3H), 3.90 (s, 3H), 4.18 (m, 2H), 4.35(m, 2H), 5.23 (m, 1H), 6.65 (d, 1H), 7.20 (dd, 1H), 7.75 (d, 1H); LRMSAPCI m/z 332 [M+H]⁺.

Preparation 41-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]azetidin-3-ylmethanesulfonate

A mixture of the product of preparation 3 (1.5 g, 4.5 mmol),acethydrazide (671 mg, 9 mmol) and trifluoroacetic acid (3 drops, cat)in tetrahydrofuran (50 mL) was heated under reflux for 4 hours. Thecooled mixture was then diluted with a mixture of water and brine,30:70, and extracted with ethyl acetate (3×50 mL). The combined organicsolution was dried over magnesium sulfate, concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 100:0 to 97.5:2.5, to afford the titlecompound as a pale brown oil in 50% yield, 720 mg. ¹H NMR (400 MHz,CDCl₃) δ: 2.24 (s, 3H), 3.04 (s, 3H), 4.02 (s, 3H), 4.14 (m, 2H), 4.37(m, 2H), 5.30 (m, 1H), 6.91 (d, 1H), 7.72 (dd, 1H), 7.18 (d, 1H); LRMSAPCI m/z 340 [M+H]⁺.

Preparation 5 2-Methoxyacetylhydrazide

Hydrazine monohydrate (9.85 mL, 202 mmol) was added to a solution ofmethyl methoxyacetate (10 mL, 101 mmol) in methanol (50 mL) and themixture was heated at 70° C. for 18 hours. The reaction mixture was thencooled to room temperature and concentrated in vacuo. The residue wasazeotroped with toluene (×2) to give a white solid. The solid wastriturated with diethyl ether and the resulting solid was dried undervacuum, at 500° C. for 30 minutes, to afford the title compound as awhite solid in 95% yield, 9.98 g. ¹H NMR (400 MHz, DMSO-d₆) δ: 3.26 (s,3H), 3.79 (s, 2H), 4.22 (bs, 2H), 8.97 (bs, 1H)

Preparation 61-[5-(Methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]azetidin-3-ylmethanesulfonate

A mixture of the product of preparation 3 (1 g, 3 mmol), the product ofpreparation 5 (629 mg, 6 mmol) and trifluoroacetic acid (3 drops) intetrahydrofuran (20 mL) was heated under reflux for 8 hours. The cooledmixture was then diluted with a mixture of water and brine, 30:70, andextracted with ethyl acetate (3×30 mL). The combined organic solutionwas dried over magnesium sulfate, concentrated in vacuo and the residuewas purified by column chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 95:5, to afford the title compound asa pale brown oil in 72% yield, 800 mg. ¹H NMR (400 MHz, CDCl₃) δ: 3.03(s, 3H), 3.27 (s, 3H), 3.98 (s, 3H), 4.06 (m, 2H), 4.20 (m, 2H), 4.32(s, 2H), 5.23 (m, 1H), 6.84 (d, 1H), 7.60 (dd, 1H), 8.17 (d, 1H); LRMSAPCI m/z 370 [M+H]⁺

Preparation 71-[5-Isopropyl-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]azetidin-3-ylmethanesulfonate

The title compound was prepared from the product of preparation 3 and2-methylpropanoic acid hydrazide (Bioorganic & Medicinal Chemistry,2003, 11, 1381), using the same method as that described for preparation6, in 30% yield. ¹H NMR (400 MHz, CDCl₃) δ: 1.22 (d, 6H), 2.67 (m, 1H),3.02 (s, 3H), 3.97 (m, 2H), 3.99 (s, 3H), 4.06 (m, 2H), 5.18 (m, 1H),6.87 (d, 1H), 7.45 (dd, 1H), 8.08 (d, 1H); LRMS APCI m/z 368[M+H]⁺.

Preparation 8 1-(Diphenylmethyl)-3-methylazetidin-3-ol

Methyl magnesium iodide (3M in diethyl ether, 1.4 mL, 4.2 mmol) wasadded dropwise to an ice-cold solution of1-(diphenylmethyl)-3-azetidinone (1 g, 4.20 mmol) in diethyl ether (25mL) and the mixture was stirred for 1 hour at 0° C. The crude reactionmixture was then purified directly by column chromatography on silicagel, eluting with dichloromethane:methanol, 100:0 to 95:5, to afford thetitle compound the title compound as a pale yellow oil in 68% yield, 730mg. ¹H NMR (CDCl₃, 400 MHz) δ: 1.54 (s, 3H), 3.02 (m, 2H), 3.22 (m, 2H),4.39 (s, 1H), 7.20 (m, 4H), 7.26 (m, 4H), 7.41 (m, 2H); LRMS ESI⁺ m/z254 [M+H]⁺.

Preparation 9 1-(Diphenylmethyl)-3-(3-fluorophenoxy)-3-methylazetidine

A mixture of 3-fluorophenol (0.2 mL, 2.2 mmol) and triphenylphosphine(648 mg, 2.5 mmol) in toluene (8 mL) was warmed to 95° C. A mixture ofthe product of preparation 8 (500 mg, 2 mmol) anddi-isopropylazodicarboxylate (0.5 mL, 2.47 mmol) in toluene (4 mL) wasthen added and reaction mixture was stirred at 95° C. for 18 hours. Thecooled reaction mixture was then concentrated in vacuo and the residuewas purified by column chromatography on silica gel, eluting withdichloromethane:methanol, 95:5, to afford the title compound as a yellowoil in 93% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 1.77 (s, 3H), 3.25 (m, 2H),3.50 (m, 2H), 4.45 (s, 1H), 6.40 (d, 1H), 6.46 (d, 1H), 6.63 (t, 1H),6.98 (m, 1H), 7.19 (m, 4H), 7.32 (m, 4H), 7.48 (m, 2H); LRMS APCI⁺ m/z348 [M+H]⁺.

Preparation 10 3-(3-Fluorophenoxy)-3-methylazetidine hydrochloride

1-Chloroethyl chloroformate (0.3 mL, 2.76 mmol) was added to anice-cooled solution of the product of preparation 9 (1.34 g, 4.43 mmol)in dichloromethane (10 mL) and mixture was heated under reflux for 3hours. The reaction mixture was then concentrated in vacuo and theresidue was re-dissolved in methanol. This solution was then heatedunder reflux for 3 hours. The reaction mixture was then cooled,concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol,95:5, to afford the title compound as a crystalline solid in 60% yield,200 mg. ¹H NMR (DMSO-d₆, 400 MHz) δ: 3.35 (s, 3H), 4.18 (m, 4H), 6.65(m, 2H), 6.84 (t, 1H), 7.35 (m, 1H); LRMS ESI⁺ m/z 182 [M+H]⁺.

Preparation 113-(3-Fluorophenoxy)-N-(6-methoxypyridin-3-yl)-3-methylazetidine-1-carbothioamide

5-Isothiocyanato-2-methoxypyridine [(172.9 mg, 1.04 mmol), J. Org. Chem.(1980), 45, 4219] was added to a solution of the product of preparation10 (200 mg, 1.04 mmol) in dichloromethane (3 mL) and the mixture wasstirred at room temperature for 18 hours. The reaction mixture wasconcentrated in vacuo to afford the crude title compound in quantitativeyield. This material was used in further reactions without anypurification. ¹H NMR (DMSO-d₆, 400 MHz) δ: 1.77 (s, 3H), 4.04 (s, 3H),4.33 (m, 2H), 4.50 (m, 2H), 6.50 (m, 2H), 6.74 (m, 2H), 7.23 (m, 1H),7.44 (dd, 1H), 8.10 (m, 1H); LRMS ESI⁺ m/z 348 [M+H]⁺.

Preparation 12 Methyl3-(3-fluorophenoxy)-N-(6-methoxypyridin-3-yl)-3-methylazetidine-1-carbimidothioate

The title compound was prepared from the product of preparation 11,using the same method as that described for preparation 3, as a paleyellow oil in 46% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 1.78 (s, 3H), 2.36(s, 3H), 3.97 (s, 3H), 4.30 (m, 2H), 4.58 (m, 2H), 6.43 (m, 2H), 6.75(m, 2H), 7.17 (d, 1H), 7.24 (m, 1H), 7.78 (d, 1H); LRMS ESI⁺ m/z 362[M+H]⁺.

Preparation 13 3-Isothiocyanato-6-methoxy-2-methylpyridine

A solution of 6-methoxy-2-methyl-3-pyridylamine [(500 mg, 3.6 mmol), WO04/062665, p 46] in dichloromethane (10 mL) was added to an ice-coldsolution of 1′1-thiocarbonyldi-2(1H)-pyridone (840 mg, 3.6 mmol) indichloromethane (10 mL) and the mixture was stirred for 18 hours. Thereaction mixture was then concentrated in vacuo and the residue waspurified by column chromatography on silica gel, eluting withdichloromethane to afford the title compound as a yellow solid in 79%yield. ¹H NMR (CDCl₃, 400 MHz) δ: 2.52 (s, 3H), 3.92 (s, 3H), 6.56 (d,1H), 7.38 (d, 1H); LRMS ESI⁺ m/z 181 [M+H]⁺.

Preparation 141-{[(6-Methoxy-2-methylpyridin-3-yl)amino]carbonothioyl}azetidin-3-ylmethanesulfonate

A mixture of the product of preparation 1 (535 mg, 2.84 mmol),preparation 13 (515 mg, 2.84 mmol) and triethylamine (0.4 mL, 2.84 mmol)in dichloromethane was stirred for at room temperature for 18 hours. Thereaction mixture was then filtered and the residue was partitionedbetween ethyl acetate and brine. The combined organic solution was driedover magnesium sulfate and concentrated in vacuo to afford the titlecompound as a pale yellow solid in 71% yield, 670 mg. ¹H NMR (CDCl₃, 400MHz) δ: 2.44 (s, 3H), 3.08 (s, 3H), 3.95 (s, 3H), 4.20 (m, 2H), 4.40 (m,2H), 5.20 (m, 1H), 6.62 (d, 1H), 7.49 (d, 1H); LRMS ESI⁺ m/z 332 [M+H]⁺.

Preparation 15 MethylN-(6-methoxy-2-methylpyridin-3-yl)-3-[(methylsulfonyl)oxy]azetidine-1-carbimidothioate

The title compound was prepared from the product of preparation 14 usingthe same method as that described for preparation 3, as a brown oil in98% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 2.34 (s, 3H), 2.46 (s, 3H), 3.06(s, 3H), 3.90 (s, 3H), 4.16 (m, 2H), 4.30 (m, 2H), 5.20 (m, 1H), 6.53(d, 1H), 7.10 (d, 1H); LRMS ESI⁺ m/z 346 [M+H]⁺.

Preparation 161-[4-(6-Methoxy-2-methylpyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]azetidin-3-ylmethanesulfonate

The title compound was prepared from the product of preparation 15 andacethydrazide, using the same method as that described for preparation4, in 35% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 2.12 (s, 3H), 2.22 (s, 3H),3.06 (s, 3H), 3.95 (s, 3H), 4.03 (m, 2H), 4.10 (m, 2H), 5.20 (m, 1H),6.70 (d, 1H), 7.37 (d, 1H); LRMS ESI⁺ m/z 346 [M+H]⁺.

Preparation 17 Piperidin-4-yl acetate

10% Pd/C (500 mg) was added to a solution of 1-benzylpiperidin-4-ylacetate [(11 g, 47 mmol), J. Org. Chem. 68(2), 613-616; 2003] in amixture of ethanol and water (90:10, 110 mL), and the mixture wasstirred at 60° C., under 60 psi of hydrogen gas for 18 hours. Thereaction mixture was then filtered through Arbocel®, washing throughwith ethanol, and the filtrate was concentrated in vacuo to afford thetitle product in 92% yield, 7.2 g. ¹H NMR (CDCl₃, 400 MHz) δ: 1.60 (m,2H), 1.81-2.18 (m, 5H), 2.78 (m, 2H), 2.95-3.18 (m, 2H), 4.82 (m, 1H);LRMS APCI⁺ m/z 145 [M+H]⁺.

Preparation 181-{[(6-Methoxypyridin-3-yl)amino]carbonothioyl}piperidin-4-yl acetate

The title compound was prepared from 5-amino-2-methoxypyridine,1′1-thiocarbonyldi-2(1H)-pyridone and the product of preparation 17,using the same method as that described for preparation 2, in 19% yield.¹H NMR (CDCl₃, 400 MHz) δ: 1.78-1.85 (m, 2H), 1.98-2.08 (m, 2H), 2.18(s, 3H), 3.79-3.87 (m, 2H), 3.95 (s, 3H), 4.02-4.12 (m, 2H), 5.01-5.09(m, 1H), 6.89 (d, 1H), 6.99 (s, 1H), 7.58 (d, 1H), 7.97 (s, 1H); LRMSAPCI m/z 310 [M+H]⁺.

Preparation 194-Hydroxy-N-(6-methoxypyridin-3-yl)piperidine-1-carbothioamide

The title compound was prepared from piperidin-4-ol,5-amino-2-methoxypyridine, and 1′1-thiocarbonyldi-2(1H)-pyridone, usingthe same method as that described for preparation 2, in 67% yield. ¹HNMR (400 MHz, CDCl₃) δ: 1.59-1.79 (m, 2H), 1.90-2.04 (m, 2H), 3.64-3.76(m, 2H), 3.93 (s, 3H), 4.00-4.10 (m, 1H), 4.14-4.22 (m, 1H), 6.78 (d,1H), 7.04-7.20 (s, 1H), 7.62 (d, 1H), 7.98 (s, 1H) LRMS APCI m/z 268[M+H]⁺

Preparation 201-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-ylacetate

Potassium tert-butoxide (0.91 g, 8.10 mmol) was added to a solution ofthe product of preparation 18 (2.28 g, 7.36 mmol) in tetrahydrofuran (20mL) and the mixture was stirred at room temperature for 30 minutes.Methyl p-toluenesulfonate (1.81 g, 8.10 mmol) was added and the mixturewas stirred for 18 hours. The reaction mixture was then concentrated invacuo and the residue was re-dissolved in dichloromethane. The solutionwas washed with sodium hydrogen carbonate solution and brine, dried overmagnesium sulfate and concentrated in vacuo to give an oil. The oil wasdissolved in tetrahydrofuran (5 mL), trifluoroacetic acid (0.28 mL, 3.68mmol) and acethydrazide (1.09 g, 14.7 mmol) were added and the mixturewas heated under reflux for 18 hours. The cooled reaction mixture wasthen concentrated in vacuo and the residue was dissolved indichloromethane and washed with sodium hydrogen carbonate solution andbrine. The organic solution was dried over magnesium sulfate andconcentrated in vacuo to afford the title compound as an oil in 49%yield, 1.2 g.

¹H NMR (CDCl₃, 400 MHz) δ: 1.57-1.70 (m, 2H), 1.79-1.90 (m, 2H), 2.01(s, 3H), 2.22 (s, 3H), 2.94-3.01 (m, 2H), 3.22-3.31 (m, 2H), 3.99 (s,3H), 4.80-4.92 (m, 1H), 6.89 (d, 1H), 7.52 (d, 1H), 8.12 (s, 1H)

Preparation 211-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-ol

A mixture of the product of preparation 20 (1.2 g, 3.62 mmol) and 1Mpotassium carbonate solution (10 mL, 10 mmol) in methanol (20 mL) wasstirred at room temperature for 24 hours. The reaction mixture was thenconcentrated in vacuo and the aqueous residue was extracted withdichloromethane. The organic solution was washed with brine, dried oversodium sulfate and concentrated in vacuo. Purification by columnchromatography on silica gel, eluting with dichloromethane:methanol,100:0 to 90:10, to afford the title compound as a solid in 45% yield,472.5 mg. ¹H NMR (CDCl₃, 400 MHz) δ: 1.41-1.55 (m, 2H), 1.71 (s, 1H),1.80-1.90 (m, 2H), 2.22 (s, 3H), 2.85-2.94 (m, 2H), 3.22-3.31 (m, 2H),3.77-3.82 (m, 1H), 3.99 (s, 3H), 6.89 (d, 1H), 7.52 (d, 1H), 8.12 (s,1H); LRMS APCI m/z 332 [M+H]⁺

Preparation 22 3-[(1-Benzylpiperidin-4-yl)oxy]-2-methylpyridine

1-Benzyl-4-hydroxypiperidine (1.5 g, 7.8 mmol) and3-hydroxy-2-methylpyridine (1.75 g, 16 mmol) were added to mixture ofpolymer supported triphenylphosphine (1 g, 3 mmol) and di-tert-butylazodicarboxylate (3.61 g, 16 mmol) in dichloromethane (10 mL) and themixture was stirred at room temperature for 3 hours. Trifluoroaceticacid (16 mL) was then added and the mixture was stirred for a furtherhour then concentrated in vacuo. The residue was suspended indichloromethane and basified with 2M sodium hydroxide solution (5 mL).The organic layer was separated, washed with brine, dried over magnesiumsulfate and concentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with dichloromethane:methanol:0.88ammonia, 90:10:1, to afford the title compound as a liquid in 51% yield,1.12 g. ¹H NMR (CDCl₃, 400 MHz) δ: 1.79-1.88 (m, 2H), 1.90-2.01 (m, 2H),2.25-2.41 (m, 2H), 2.44 (s, 3H), 2.64-2.78 (m, 2H), 3.53 (s, 2H),4.28-4.39 (m, 1H), 7.00-7.09 (m, 2H), 7.19-7.38 (m, 5H), 8.14 (m, 1H);LRMS APCI m/z 283 [M+H]⁺.

Preparation 23 2-Methyl-3-(piperidin-4-yloxy)pyridine

10% Pd/C (100 mg, cat) was added to a solution of the product ofpreparation 22 (1.12 g, 3.96 mmol) in a mixture of ethanol and water(90:10, 1 mL) and the mixture was stirred at 60° C., under 60 psi ofhydrogen gas for 18 hours. The reaction mixture was then filteredthrough Arbocel®, and the filtrate was concentrated in vacuo. Theresidue was re-dissolved in ethanol/water (90:10, 1 mL) and 10% Pd/C(100 mg, cat) was added. The reaction mixture was then stirred at 60°C., under 60 psi of hydrogen gas. After 18 hours, the mixture wasfiltered through Arbocel®, washing through with ethanol, and thefiltrate was concentrated in vacuo. Trituration of the residue withdiethyl ether afforded the title compound as a solid in 74% yield, 565mg. ¹H NMR (CDCl₃, 400 MHz) δ: 2.10-2.20 (m, 2H), 2.30-2.41 (m, 2H),2.49 (s, 3H), 3.29-3.40 (m, 4H), 4.61-4.70 (m, 1H), 7.02-7.13 (m, 2H),8.12 (m, 1H); LRMS APCI⁺ m/z 193 [M+H]⁺.

Preparation 24N-(6-Methoxypyridin-3-yl)-4-[(2-methylpyridin-3-yl)oxy]piperidine-1-carbothioamide

5-Isothiocyanato-2-methoxypyridine [(172.9 mg, 1.04 mmol), J. Org. Chem.(1980), 45, 4219] was added to a solution of the product of preparation23 (200 mg, 1.04 mmol) in dichloromethane (3 mL) and the mixture wasstirred at room temperature for 72 hours. The resulting precipitate wasfiltered off, washing through with water, dichloromethane and diethylether, to afford a portion of the title compound. The filtrate was thendiluted with water and acidified with 10% citric acid. The aqueous layerwas separated, basified with sodium hydrogen carbonate solution andextracted with dichloromethane. The organic layer was washed with brine,dried over sodium sulfate and concentrated in vacuo to afford furthertitle compound as a white solid. The two solids were combined to give48% overall yield (180 mg). ¹H NMR (DMSO-d₆, 400 MHz) δ: 1.69-1.81 (m,2H), 1.95-2.09 (m, 2H), 2.48 (s, 3H), 3.83 (s, 3H), 3.87-3.98 (m, 2H),4.05-4.19 (m, 2H), 4.83-4.90 (m, 1H), 7.44-7.51 (m, 1H), 7.56-7.62 (m,1H), 7.79-7.85 (m, 1H), 7.93 (s, 1H), 8.19 (d, 1H), 9.32 (s, 1H); LRMSAPCI m/z 359 [M+H]⁺.

Preparation 25 2-[(1-Benzylpiperidin-4-yl)oxy]-3-methylpyridine

Potassium tert-butoxide (1.08 g, 8.62 mmol) was added to a solution of1-benzyl-4-hydroxypiperidine (1.5 g, 7.84 mmol) in dimethylsulfoxide (5mL) and the mixture was stirred at room temperature for 1 hour.2-Fluoro-3-methylpyridine (957 mg, 8.62 mmol) was then added and thereaction mixture was stirred at room temperature for 3 hours. Themixture was partitioned between ethyl acetate and water, and the organiclayer was separated and washed with sodium hydrogen carbonate solutionand brine. The organic solution was then dried over magnesium sulfateconcentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol,100:0 to 70:30, to afford the title compound as a solid in 85% yield,1.9 g. ¹H NMR (CDCl₃, 400 MHz): 1.79-1.94 (m, 2H), 1.98-2.09 (m, 2H),2.17 (s, 3H), 2.37-2.47 (m, 2H), 2.68-2.77 (m, 2H), 3.61-3.51 (bs, 2H),5.12-5.20 (m, 1H), 6.74 (m, 1H), 7.24-7.37 (m, 6H), 7.95 (m, 1H); LRMSAPCI m/z 283 [M+H]⁺.

Preparation 26 4-[(1-Benzylpiperidin-4-yl)oxy]pyridine

The title compound was prepared from 1-benzyl-4-hydroxypiperidine and4-chloropyridine (979 mg, 8.62 mmol), using the same method as thatdescribed for preparation 25, as an oil in 52% yield. ¹H NMR (CDCl₃, 400MHz): 1.81-1.96 (m, 2H), 1.98-2.18 (m, 2H), 2.30-2.48 (m, 2H), 2.70-2.83(m, 2H), 3.52-3.70 (m, 2H), 4.40-4.50 (m, 1H), 6.72-6.80 (m, 2H),7.22-7.39 (m, 5H), 8.40 (m, 2H); LRMS APCI m/z 269 [M+H]⁺.

Preparation 27 tert-butyl4-[(2,3-dimethylpyridin-4-yl)oxy]piperidine-1-carboxylate

Potassium tert-butoxide (4.70 g, 42 mmol) was added to a solution of1-Boc-4-hydroxypiperidine (4.05 g, 20.1 mmol) in dimethylsulfoxide (20mL) and the mixture was stirred at room temperature for 1 hour.4-Chloro-2,3-dimethylpyridine (3.58 g, 20.1 mmol) was then added and thereaction mixture was stirred at 50° C. for 18 hours. The mixture waspartitioned between ethyl acetate and water, and the organic layer wasseparated and washed with sodium hydrogen carbonate solution and brine.The organic solution was then dried over magnesium sulfate concentratedin vacuo and the residue was purified by column chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to94:6:0.6, to afford the title compound as an oil in 39% yield, 2.4 g.

¹H NMR (CDCl₃, 400 MHz) δ: 1.44 (s, 9H), 1.75-1.85 (m, 2H), 1.87-1.95(m, 2H), 2.15 (s, 3H), 2.50 (s, 3H), 3.42-3.53 (m, 2H), 3.56-3.65 (m,2H), 4.57-4.62 (m, 1H), 6.64 (d, 1H), 8.21 (d, 1H); LRMS APCI m/z 307[M+H]⁺.

Preparation 28 tert-Butyl4-[(3-methylpyridin-4-yl)oxy]piperidine-1-carboxylate

The title compound was prepared from 1-Boc-4-hydroxypiperidine and4-chloro-3-methylpyridine hydrochloride, using a similar method topreparation 27. The reaction mixture was stirred for 72 hours to affordthe title compound the desired product in 87% yield. ¹H NMR(CDCl₃, 400MHz) δ: 1.44 (s, 9H), 1.75-1.85 (m, 2H), 1.87-1.97 (m, 2H), 2.18 (s,3H), 3.42-3.53 (m, 2H), 3.56-3.65 (m, 2H), 4.57-4.65 (m, 1H), 6.72 (d,1H), 8.29 (s, 1H), 8.35 (d, 1H); LRMS APCI m/z 293 [M+H]⁺.

Preparation 29 3-Methyl-2-(piperidin-4-yloxy)pyridine

The title compound was prepared from the product of preparation 25,using the same method as that of preparation 17, as a gum in 62% yield.¹H NMR (CDCl₃, 400 MHz) δ: 1.79-1.94 (m, 2H), 1.96-2.20 (m, 5H),2.89-3.00 (m, 2H), 3.18-3.26 (m, 2H), 5.24-5.35 (m, 1H), 6.74 (m, 1H),7.38 (m, 1H), 7.95 (m, 1H); LRMS APCI m/z 193 [M+H]⁺.

Preparation 30 4-(Piperidin-4-yloxy)pyridine

The title compound was prepared from the product of preparation 26,using the same method as that described for preparation 23, as a solidin 82% yield.

¹H NMR (CDCl₃, 400 MHz) δ: 1.94-2.02 (m, 2H), 2.20-2.29 (m, 2H),3.06-3.18 (m, 2H), 3.22-3.32 (m, 2H), 4.60-4.67 (m, 1H), 6.80 (d, 2H),8.43 (d, 2H); LRMS APCI⁺ m/z 179 [M+H]⁺.

Preparation 31 2,3-Dimethyl-4-(piperidin-4-yloxy)pyridinedihydrochloride

A solution of the product of preparation 27 (1.3 g, 4.24 mmol) inhydrochloric acid (4M in dioxan, 5 mL) was stirred for 2 hours at roomtemperature. The reaction mixture was then concentrated in vacuo and theresidue as azeotroped with toluene to afford the title compound as awhite solid in 91% yield, 800 mg. ¹H NMR (DMSO-d₆, 400 MHz) δ: 1.91-2.02(m, 2H), 2.15-2.24 (m, 5H), 2.48 (s, 3H), 3.09-3.17 (m, 2H), 3.18-3.24(m, 2H), 5.09-5.15 (m, 1H), 7.59 (d, 1H), 8.58 (d, 1H), 9.19-9.38 (m,2H); LRMS APCI⁺ m/z 207 [M+H]⁺

Preparation 32 3-Methyl-4-(piperidin-4-yloxy)pyridine dihydrochloride

The title compound was prepared from the product of preparation 28,using the same method as that described for 31, as a white solid in 82%yield. ¹H NMR (DMSO-d₆, 400 MHz) 1.92-2.05 (m, 2H), 2.16-2.24 (m, 5H),3.11-3.19 (m, 4H), 5.15-5.17 (m, 1H), 7.73 (d, 1H), 8.64 (s, 1H), 8.72(m, 1H), 9.39-9.57 (m, 2H); LRMS APCI⁺ m/z 193 [M+H]⁺.

Preparation 33N-(6-Methoxypyridin-3-yl)-4-[(3-methylpyridin-2-yl)oxy]piperidine-1-carbothioamide

The title compound was prepared from the product of preparation 29 and5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219),using a similar method to that of preparation 24. Tlc analysis showedthe reaction to be complete after 18 hours (c.f. 72 hours in preparation24), affording the desired product as a solid in 58% yield. ¹H NMR(CDCl₃, 400 MHz): 1.93-2.00 (m, 2H), 2.05-2.18 (m, 2H), 2.20 (s, 3H),3.95 (s, 3H), 4.02-4.09 (m, 4H), 5.40-5.45 (m, 1H), 6.72-6.81 (m, 2H),7.01 (bs, 1H), 7.40 (m, 1H), 7.59 (m, 1H), 7.95-7.99 (m, 2H); LRMS APCIm/z 359 [M+H]⁺.

Preparation 34N-(6-Methoxypyridin-3-yl)-4-(pyridin-4-yloxy)piperidine-1-carbothioamide

5-Isothiocyanato-2-methoxypyridine [(829 mg, 4.99 mmol), J. Org. Chem.(1980), 45, 4219] was added to a solution of the product of preparation30 (890 mg, 4.99 mmol) in dichloromethane (10 mL) and the mixture wasstirred at room temperature for 20 hours. The resulting precipitate wasfiltered off, washing through with diethyl ether, to afford the titlecompound as a white solid in 43% yield, 738 mg. ¹H NMR (CDCl₃, 400 MHz)δ: 1.95-2.05 (m, 2H), 2.06-2.15 (m, 2H), 3.93-4.01 (m, 5H), 4.03-4.12(m, 2H), 4.72-4.79 (m, 1H), 6.75-6.85 (m, 3H), 7.12 (m, 1H), 7.58 (m,1H), 7.98 (m, 1H), 8.40-8.44 (m, 2H); LRMS APCI m/z 345 [M+H]⁺.

Preparation 35N-(6-methoxypyridin-3-yl)-4-(2-methylphenoxy)piperidine-1-carbothioamide

5-Isothiocyanato-2-methoxypyridine [(829 mg, 4.99 mmol), J. Org. Chem.(1980), 45, 4219] was added to a solution of4-(2-methylphenoxy)-piperidine hydrochloride [(990 mg, 4.3 mmol), J.Med. Chem. (1978), 21, 309] and N,N-diisopropylethylamine (0.79 mL, 4.7mmol) in dichloromethane (10 mL) and the mixture was stirred for 3 hoursat room temperature. The organic solution was then diluted withdichloromethane and washed with sodium hydrogen carbonate solution andbrine. The organic solution was dried over magnesium sulfate andconcentrated in vacuo. Trituration of the residue with diethyl etherafforded the title compound as a solid in 85% yield, 1.3 g. LRMS APCIm/z 358 [M+H]⁺.

Preparation 364-[(2,3-Dimethylpyridin-4-yl)oxy]-N-(6-methoxypyridin-3-yl)piperidine-1-carbothioamide

5-Isothiocyanato-2-methoxypyridine [(476 mg, 2.86 mmol), J. Org. Chem.(1980), 45, 4219] was added to a solution of the product of preparation31 (800 mg, 2.86 mmol) and N,N-diisopropylethylamine (1.45 mL, 8.58mmol) in dichloromethane (10 mL) and the mixture was stirred for 3 hoursat room temperature. The reaction mixture was then partitioned betweendichloromethane and water and the organic layer was separated and washedwith sodium hydrogen carbonate solution and brine. The organic solutionwas dried over magnesium sulfate and concentrated in vacuo. Triturationof the residue with diethyl ether afforded the title compound as a solidin 80% yield, 857 mg. ¹H NMR (CDCl₃, 400 MHz) δ: 1.92-2.13 (m, 4H), 1.97(s, 3H), 2.50 (s, 3H), 3.88-3.97 (m, 5H), 4.10-4.19 (m, 2H), 4.69-4.75(m, 1H), 6.61 (d, 1H), 6.77 (m, 1H), 7.10 (s, 1H), 7.58 (dd, 1H), 7.98(m, 1H), 8.22 (m, 1H); LRMS APCI m/z 373 [M+H]⁺.

Preparation 37N-(6-Methoxypyridin-3-yl)-4-[(3-methylpyridin-4-yl)oxy]piperidine-1-carbothioamide

The title compound was prepared from the product of preparation 32 usingthe same method as that described for 36, as a white solid in 63% yield.¹H NMR (CDCl₃, 400 MHz) δ: 1.94-2.01 (m, 2H), 2.02-2.13 (m, 2H), 2.19(s, 3H), 3.85-3.97 (m, 5H), 4.08-4.15 (m, 2H), 4.72-4.79 (m, 1H),6.71-6.6.74 (m, 2H), 7.16 (m, 1H), 7.56 (dd, 1H), 7.95 (m, 1H), 8.25 (m,1H), 8.34 (m, 1H); LRMS APCI m/z 359 [M+H]⁺

Preparation 38 MethylN-(6-methoxypyridin-3-yl)-4-[(3-methylpyridin-2-yl)oxy]piperidine-1-carbimidothioate

Potassium tert-butoxide (160 mg, 1.43 mmol) was added to a solution ofthe product of preparation 33 (465 mg, 1.30 mmol) in tetrahydrofuran (5mL) and the mixture was stirred at room temperature for 1 hour. Methylp-toluenesulfonate (271 mg, 1.43 mmol) was then added and the mixturewas stirred for 3 hours at room temperature. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between with waterand dichloromethane. The organic layer was separated and washed withsodium hydrogen carbonate solution and brine. The organic solution wasthen dried over sodium sulfate and concentrated in vacuo to afford thetitle compound as a yellow oil in 93% yield, 450 mg. ¹H NMR (CDCl₃, 400MHz) δ: 1.81-1.95 (m, 2H), 2.05-2.15 (m, 5H), 2.20 (s, 3H), 3.59-3.65(m, 2H), 3.72-3.79 (m, 2H), 3.95 (s, 3H), 5.38-5.43 (m, 1H), 6.69-6.81(m, 1H), 6.77-7.01 (m, 1H), 7.20 (dd, 1H), 7.40 (m, 1H), 7.76 (m, 1H),7.79 (m, 1H); LRMS APCI m/z 373 [M+H]⁺

Preparation 39 MethylN-(6-methoxypyridin-3-yl)-4-(2-methylphenoxy)piperidine-1-carbimidothioate

The title compound was prepared from the product of preparation 35 andmethyl toluenesulfonate, using the same method as that described for 38,as an oil in quantitative yield. LRMS ESI m/z 394 [M+H]⁺.

Preparation 40 Methyl4-hydroxy-N-(6-methoxypyridin-3-yl)piperidine-1-carbimidothioate

The title compound was prepared from the product of preparation 19,using the same method as that of preparation 38. The crude compound waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol, 95:5, to afford the title compound as acolourless oil in 57% yield. ¹H NMR (CDCl₃, 400 MHz): 1.50 (d, 1H),1.55-1.65 (m, 2H), 1.92-2.00 (m, 2H), 2.10 (s, 3H), 3.21-3.29 (m, 2H),3.89-3.99 (m, 4H), 4.00-4.09 (m, 2H), 6.65 (d, 1H), 7.18 (d, 1H), 7.71(s, 1H); LRMS APCI m/z 282 [M+H]⁺.

Preparation 41 Methyl4-[(2,3-dimethylpyridin-4-yl)oxy]-N-(6-methoxypyridin-3-yl)piperidine-1-carbimidothioate

The title compound was prepared from the product of preparation 36,using the same method as that of preparation 38, as a colourless oil inquantitative yield. ¹H NMR (CDCl₃, 400 MHz): 1.82-1.95 (m, 2H),2.01-2.10 (m, 2H), 2.12 (s, 3H), 2.18 (s, 3H), 2.50 (s, 3H), 3.65-3.82(m, 4H), 3.82 (s, 3H), 4.63-4.69 (m, 1H), 6.62 (d, 1H), 6.69 (d, 1H),7.18 (dd, 1H), 7.76 (m, 1H), 8.22 (m, 1H); LRMS APCI m/z 387 [M+H]⁺.

Preparation 421-[5-(Methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-4-ol

The title compound was prepared from the product of preparation 40,using the same method as that described for preparation 4, in 55% yield.¹H NMR (CDCl₃, 400 MHz): 1.41 (d, 1H), 1.47-1.55 (m, 2H), 1.77-1.85 (m,2H), 2.84-2.95 (m, 2H), 3.28-3.35 (m, 5H), 3.73-4.01 (m, 1H), 3.98 (s,3H), 4.30 (s, 2H), 6.82 (d, 1H), 7.62 (m, 1H), 8.22 (m, 1H); LRMS APCIm/z 320 [M+H]⁺.

Preparation 43 1-Benzyl-4-(2-chlorophenoxy)piperidine

Triphenylphosphine (1.91 g, 7.31 mmol) was added to an ice-cooledsolution of di-isopropylazodicarboxylate (1.48 g, 7.31 mmol) indichloromethane (15 mL) and the mixture was stirred for 10 minutes. Asolution of 2-chlorophenol (806 mg, 6.27 mmol) and1-benzyl-4-hydroxypiperidine (1 g, 5.22 mmol) in dichloromethane (5 mL)was then added dropwise to the ice-cooled reaction mixture and stirringcontinued for a further 72 hours. The reaction mixture was thenconcentrated in vacuo and the residue was dissolved in diethyl ether andextracted with saturated citric acid solution (5×10 mL). The combinedaqueous solution was then basified with sodium hydroxide and extractedwith dichloromethane (2×20 mL). The combined organic solution was driedover magnesium sulfate and concentrated in vacuo to afford the titlecompound as a clear oil in 89% yield, 1.4 g. ¹H NMR (CDCl₃, 400 MHz):1.85-1.95 (m, 2H), 1.97-2.08 (m, 2H), 2.32-2.47 (m, 2H), 3.58 (s, 2H),4.46-4.34 (m, 1H), 6.87-6.95 (m, 2H), 7.16-7.22 (m, 1H), 7.20 (dd, 1H),7.26-7.37 (m, 6H)

Preparation 44 1-Benzyl-4-(3,5-difluorophenoxy)piperidine

The title compound was prepared from 1-benzyl-4-hydroxypiperidine and3,5-difluorophenol, using the same method as that described forpreparation 43. The crude compound was purified by column chromatographyon silica gel, eluting with dichloromethane:methanol, 95:5, to affordthe desired product in 63% yield. LRMS APCI m/z 304 [M+H]⁺

Preparation 45 4-(2-Chlorophenoxy)piperidine hydrochloride

1-Chloroethyl chloroformate (0.95 g, 6.65 mmol) was added to anice-cooled solution of the product of preparation 43 (1.34 g, 4.43 mmol)and “proton sponge”, 1,8-bis(dimethylamino)naphthalene, (951 mg, 4.43mmol) in dichloromethane (15 mL) and mixture was stirred for 45 minutesat room temperature. The reaction mixture was then washed with 10%citric acid solution (2×5 mL) and brine (5 mL), dried over magnesiumsulfate and concentrated in vacuo. The residue was then dissolved inmethanol and heated under reflux for 30 minutes. The reaction mixturewas cooled to room temperature concentrated in vacuo, and the residuewas triturated with diethyl ether to afford the title compound as awhite solid in 69% yield, 890 mg. ¹H NMR (DMSO-d₆, 400 MHz) δ: 1.80-1.95(m, 2H), 2.05-2.20 (m, 2H), 3.05-3.30 (m, 4H), 4.70-4.85 (m, 1H),6.90-7.00 (m, 1H), 7.15-7.30 (m, 2H), 7.35-7.45 (m, 1H), 8.70-9.20 (brm,2H); LRMS APCI m/z 212/248 [M+H]⁺

Preparation 46 4-(3,5-Difluorophenoxy)piperidine hydrochloride

The title compound was prepared from the product of preparation 44,using the same method as that described for preparation 45, as a whitesolid in quantitative yield. ¹H NMR (DMSO-d₆, 400 MHz) δ: 1.77-1.88 (m,2H), 2.02-2.18 (m, 2H), 2.95-3.10 (m, 2H), 3.13-3.23 (m, 2H), 4.62-4.71(m, 1H), 6.73-6.82 (m, 3H), 9.00-9.19 (brm, 2H); LRMS APCI m/z 214[M+H]⁺.

Preparation 474-(2-Chlorophenoxy)-N-(6-methoxypyridin-3-yl)piperidine-1-carbothioamide

The title compound was prepared from the product of preparation 45 and5-isothiocyanato-2-methoxypyridine [(829 mg, 4.99 mmol), J. Org. Chem.(1980), 45, 4219], using the same procedure as that described for 35.The crude compound was purified by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 99:1:0.5,to afford the title compound as a white solid in 74% yield. ¹H NMR(CDCl₃, 400 MHz) δ: 1.95-2.10 (m, 4H), 3.90-4.10 (m, 5H), 4.20-4.30 (m,2H), 4.65-4.75 (m, 1H), 6.80 (d, 1H), 6.90-7.05 (m, 3H), 7.15-7.30 (m,1H), 7.37 (d, 1H), 7.75-7.90 (m, 1H), 8.05 (s, 1H)

Preparation 484-(3,5-difluorophenoxy)-N-(6-methoxypyridin-3-yl)piperidine-1-carbothioamide

The title compound was prepared from the product of preparation 46 and5-Isothiocyanato-2-methoxypyridine [(829 mg, 4.99 mmol), J. Org. Chem.(1980), 45, 4219], using the same procedure as that described for 35, asa solid in 85% yield. LRMS APCI m/z 380 [M+H]⁺

Preparation 49 tert-Butyl4-[methyl(pyridin-2-yl)amino]piperidine-1-carboxylate

A mixture of tert-butyl 4-(methylamino)piperidine-1-carboxylate (WO03/089412, p 22), (2 g, 9.33 mmol), 2-bromopyridine (1.35 mL, 13.99mmol) and N,N-diisopropylethylamine (2.5 mL, 13.99 mmol) was heated at130° C. for 3 hours. Potassium carbonate (2 g, 14 mmol) was added andthe reaction mixture was heated at 130° C. for a further 8 hours.2-Bromopyridine (1 mL, 10.36 mmol) was then added to the mixture andheating continued at 130° C. for 36 hours. The reaction mixture was thencooled and partitioned between ethyl acetate (30 mL) and water (15 mL).The organic layer was separated and extracted with saturated citric acidsolution (2×15 mL), and the combined aqueous solution was basified withsodium hydrogen carbonate and extracted with dichloromethane (2×30 mL).The combined organic solution was dried over magnesium sulfate,concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with ethyl acetate:pentane, 0:100to 50:50, to afford the title compound in 24% yield, 646 mg. ¹H NMR(CDCl₃, 400 MHz) δ: 1.45 (s, 9H), 1.55-1.70 (m, 4H), 2.78-2.90 (m, 5H),4.10-4.30 (m, 2H), 4.65-4.80 (m, 1H), 6.45-6.55 (m, 2H), 7.40-7.45 (m,1H), 8.10-8.15 (m, 1H); LRMS APCI m/z 292 [M+H]⁺.

Preparation 50 N-methyl-N-piperidin-4-ylpyridin-2-amine dihydrochloride

Hydrogen chloride gas was passed through an ice-cold solution of theproduct of preparation 49 (640 mg, 2.19 mmol) in dichloromethane (10 mL)until saturation was reached. The reaction mixture was then stirred atroom temperature for 18 hours before the solvent was removed underreduced pressure. The residue was azeotroped with dichloromethane (×3),dissolved in methanol and heated under reflux for 5 minutes. Thereaction mixture was then concentrated in vacuo and the residue wastriturated with diethyl diethyl ether, and dried under vacuum at 60° C.to afford the title compound as a solid in 95% yield, 550 mg. ¹H NMR(CDCl₃, 400 MHz) δ: 1.70-1.90 (m, 2H), 2.00-2.20 (m, 2H), 2.70-3.20 (m,5H), 3.25-3.80 (m, 2H), 4.50-4.70 (m, 1H), 6.80-7.00 (m, 1H), 7.20-7.50(m, 1H), 7.90-8.20 (m, 1H), 8.90-9.40 (m, 2H); LRMS APCI m/z 192 [M+H]⁺.

Preparation 51N-(6-Methoxypyridin-3-yl)-4-[methyl(pyridin-2-yl)amino]piperidine-1-carbothioamide

The title compound was prepared from 5-amino-2-methoxypyridine,1′1-thiocarbonyldi-2(1H)-pyridone and the product of preparation 50,using the same method as that described for preparation 2, inquantitative yield. ¹H NMR (CDCl₃, 400 MHz) δ: 1.78-2.10 (m, 4H), 2.84(s, 3H), 3.19-3.31 (m, 2H), 3.94 (s, 3H), 4.77-4.85 (m, 2H), 4.96-5.15(m, 1H), 6.50 (d, 1H), 6.58 (m, 1H), 6.74 (d, 1H), 7.04 (m, 1H), 7.45(m, 1H), 7.59 (m, 1H), 7.99 (m, 1H), 8.15 (m, 1H); LRMS APCI m/z 358[M+H]⁺.

Preparation 52 tert-Butyl 4-(methylamino)piperidine-1-carboxylate

10% Pd/C (2 g) was added to a solution of tert-butyl4-oxopiperidine-1-carboxylate (20 g, 100 mmol) in methylamine (33% inethanol, 10 mL) and the mixture was stirred at room temperature, under60 psi of hydrogen, for 18 hours. The reaction mixture was then filteredthrough Arbocel® and the filtrate was concentrated in vacuo. The residuewas azeotroped with dichloromethane (×3) and the dried under vacuum for72 hours to afford the title compound as a solid in 98% yield, 21.1 g.LRMS APCI m/z 215 [M+H]⁺.

Preparation 53 tert-Butyl4-[[(benzyloxy)carbonyl](methyl)amino]piperidine-1-carboxylate

N-(Benzyloxycarbonyloxy)succinimide (5.5 g, 22.16 mmol) was addedportionwise to a solution of the product of preparation 52 (5 g, 23.33mmol) in dichloromethane (50 mL) and the mixture was stirred at roomtemperature for 18 hours. The reaction mixture was then washed withwater (2×20 mL), saturated citric acid solution (20 mL) and brine (20mL). The organic solution was dried over magnesium sulfate, concentratedin vacuo and the residue was triturated in pentane to afford the titlecompound as a solid in 81% yield, 6.63 g. ¹H NMR (CDCl₃, 400 MHz) δ:1.40-1.80 (m, 13H), 2.60-3.00 (m, 5H), 3.95-4.40 (m, 3H), 5.15 (s, 2H),7.20-7.50 (m, 5H)

Preparation 54 Benzyl methyl(piperidin-4-yl)carbamate

Trifluoroacetic acid (30 mL) was added to an ice-cooled solution of theproduct of preparation 53 (6.6 g, 19 mmol) in dichloromethane (30 mL)and the reaction was stirred for 1 hour, allowing the temperature torise to 25° C. The reaction mixture was then concentrated in vacuo andthe residue was partitioned between ethyl acetate (30 mL) and 1M sodiumhydroxide solution (20 mL). The organic layer was separated, washed withsaturated 1M sodium hydroxide solution and brine, dried over magnesiumsulfate and concentrated in vacuo. The residue was then azeotroped withtoluene (×2) to afford the title compound as an oil in quantitiativeyield, 4.64 g. ¹H NMR (CDCl₃, 400 MHz) δ: 1.55-1.75 (m, 4H), 2.15-2.55(brm, 1H), 2.60-2.90 (m, 5H), 3.10-3.25 (m, 2H), 3.80-4.40 (m, 1H), 5.15(s, 2H), 7.20-7.45 (m, 5H); LRMS APCI m/z 249 [M+H]⁺.

Preparation 55 Benzyl(1-{[(6-methoxypyridin-3-yl)amino]carbonothioyl}piperidin-4-yl)methylcarbamate

The title compound was prepared from 5-amino-2-methoxypyridine,1′1-thiocarbonyldi-2(1H)-pyridone and the product of preparation 54,using the same method as that described for preparation 2, in 77% yield.¹H NMR (CDCl₃, 400 MHz) δ: 1.70-1.90 (m, 4H), 2.75-2.90 (brs, 3H),3.00-3.20 (m, 2H), 3.95 (s, 3H), 4.05-4.50 (m, 1H), 4.70-4.90 (m, 2H)5.15 (s, 2H), 6.70-6.80 (d, 1H), 7.05-7.15 (brs, 1H), 7.30-7.45 (m, 5H),7.50-7.60 (d, 1H), 7.95 (s, 1H); LRMS APCI m/z 415 [M+H]⁺.

Preparation 56 Benzyl{1-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-yl}methylcarbamate

The title compound was prepared from the product of preparation 55,methyl tosylate and acethydrazide, using the same procedure as thatdescribed for preparation 20. The crude compound was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol,100:0 to 93:7, to afford the title compound in 67% yield. ¹H NMR (CDCl₃,400 MHz) δ: 1.50-1.80 (m, 4H), 2.20 (s, 3H), 2.70-3.00 (m, 5H),3.30-3.45 (m, 2H), 4.00 (s, 3H), 4.05-4.20 (m, 1H), 5.10 (s, 2H),6.85-6.95 (m, 1H), 7.20-7.40 (m, 5H), 7.45-7.55 (m, 1H), 8.10 (s, 1H);LRMS APCI m/z 437 [M+H]⁺.

Preparation 571-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]-N-methylpiperidin-4-amine

10% Pd/C (200 mg) was added to a solution of the product of preparation56 (2.13 g, 4.88 mmol) in a mixture of ethanol (25 mL) and hydrochloricacid (2.5 mL) and the reaction mixture was stirred at room temperature,under 60 psi of hydrogen, for 80 hours. The reaction mixture was thenfiltered through Arbocel® and the filtrate was concentrated in vacuo.The residue was partitioned between dichloromethane (50 mL) andsaturated sodium carbonate solution (20 mL), and the aqueous layer wasseparated and extracted with dichloromethane (3×10 mL). The combinedorganic solution was dried over magnesium sulfate concentrated in vacuoto afford the title compound as a foam in 87% yield, 1.28 g.

LRMS APCI m/z 303 [M+H]⁺.

Preparation 58 MethylN-(6-methoxypyridin-3-yl)-4-(pyridin-4-yloxy)piperidine-1-carbimidothioate

The title compound was prepared from the product of preparation 34 andmethyl toluenesulfonate, using the same method as that described for 38,as an oil in 99% yield. LRMS APCI m/z 359 [M+H]⁺.

Preparation 59 2-(Piperidin-4-yloxy)benzonitrile

1-Boc-4-hydroxypiperidine (20 g, 99.35 mmol) and 2-cyanophenol (11.82 g,99.35 mmol) were added to mixture of triphenylphosphine (26.06 g, 99.35mmol) and di-tert-butyl azodicarboxylate (19.56 mL, 99.35 mmol) intetrahydrofuran (800 mL) and the mixture was stirred at room temperaturefor 18 hours. The reaction mixture was then concentrated in vacuo andthe residue was taken up in hydrochloric acid (4M in dioxane, 300 mL).The reaction mixture was stirred at room temperature for 18 hours andwas then concentrated in vacuo. The residue was partitioned betweenwater and ethyl acetate and the aqueous layer was separated and washedwith ethyl acetate (2×100 mL). The aqueous solution was then basifiedwith 2M sodium hydroxide solution and then extracted with diethyl ether(3×100 mL). The combined organic solution was dried over magnesiumsulfate and concentrated in vacuo to afford the title compound as awhite solid in quantitative yield. LRMS ESI m/z 203 [M+H]⁺.

Preparation 604-(2-Cyanophenoxy)-N-(6-methoxypyridin-3-yl)piperidine-1-carbothioamide

The title compound was prepared from the product of preparation 59 and5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219),using the same method as that described for preparation 35, as a whitesolid in 75% yield

LRMS APCI m/z 369 [M+H]⁺.

Preparation 61 Methyl4-(2-cyanophenoxy)-N-(6-methoxypyridin-3-yl)piperidine-1-carbimidothioate

The title compound was prepared from the product of preparation 60 andmethyl toluenesulfonate, using the same method as that described for 38.The crude product was the triturated to afford the title compound as awhite solid in 73% yield. LRMS APCI m/z 383 [M+H]⁺

Preparation 62 1-(Diphenylmethyl)-3-phenoxyazetidine

Phenol (6.68 g, 75 mmol) was added to a suspension of sodium hydride(60% dispersion in mineral oil, 2.82 g, 75 mmol) in toluene (50 mL) andthe mixture was heated at 60° C. for 2 hours. The temperature was thenincreased to 80° C. and a solution of 1-(diphenylmethyl)-3-azetidinylmethanesulfonate (15 g, 47 mol) in toluene (150 mL) was added dropwise.The reaction mixture was stirred for 2 hours at 80° C., cooled thenwashed with water and dilute sodium hydroxide solution. The organicsolution was dried over magnesium sulfate, concentrated in vacuo and theresidue was re-crystallised from water/isopropanol to afford the titlecompound as a solid in 84% yield, 12.4 g. LRMS APCI m/z 316 [M+H]⁺.

Preparation 63 3-Phenoxyazetidine

10% Pd(OH)₂/C (500 mg) was added to a solution of the product ofpreparation 62 (10 g, 37 mmol) in ethanol (160 mL), and the mixture wasstirred at 80° C., under 45 psi of hydrogen gas, for 18 hours. Thereaction mixture was then filtered through Arbocel®, washing throughwith ethanol, and the filtrate was concentrated in vacuo. Trituration ofthe residue pentane afforded the title compound in 69% yield, 3.81 g.LRMS APCI m/z 150 [M+H]⁺

Preparation 64N-(6-Methoxypyridin-3-yl)-3-phenoxyazetidine-1-carbothioamide

The title compound was prepared from the product of preparation 63 and5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219),using the same method as that described for preparation 35, in 77%yield.

LRMS ESI m/z 316 [M+H]⁺

Preparation 65 MethylN-(6-methoxypyridin-3-yl)-3-phenoxyazetidine-1-carbimidothioate

The title compound was prepared from the product of preparation 64 andmethyl p-toluenesulfonate, using the same method as that described forpreparation 3, in 44% yield. LRMS ESI m/z 330 [M+H]⁺.

Preparation 66 2-[(Dimethylamino)methyl]-3,5-difluorophenol

Potassium carbonate (7.82 g, 56.73 mmol) was added to a solution of3,5-difluorophenol (4.92 g, 37.82 mmol) in acetonitrile (50 mL).N,N-Dimethylmethyleneiminium iodide (7.34 g, 39.71 mmol) was added andthe mixture was stirred at room temperature for 2 hours. The resultingprecipitate was filtered off, washing through with ethyl acetate and thefiltrate was partitioned between ethyl acetate (30 mL) and water (15mL). The organic layer was separated and extracted with saturated citricacid solution (2×15 mL). The combined aqueous solution was basified topH 7 with solid sodium hydrogen carbonate and extracted withdichloromethane (2×30 mL). The combined organic solution was dried overmagnesium sulfate and concentrated in vacuo to afford the title compoundas a clear oil in 54% yield, 3.8 g. LRMS APCI m/z 188 [M+H]⁺.

Preparation 67 2-(Acetyloxy)-4,6-difluorobenzyl acetate

Acetic anhydride (5.18 g, 50.75 mmol) was added to a solution of theproduct of preparation 66 (3.80 g, 20.30 mmol) in toluene (25 mL) andthe mixture was heated under reflux for 1 hour. The reaction mixture wasthen cooled to room temperature and concentrated in vacuo. The residuewas dissolved in ethyl acetate (20 mL), washed with water (×2) andbrine, dried over magnesium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with dichloromethane:methanol 100:0 to 98:2, afforded the titlecompound in 61% yield, 3 g. ¹H NMR (400 MHz, CDCl₃) δ: 2.05 (s, 3H),2.35 (s, 3H), 5.08 (s, 2H), 6.70-6.80 (m, 2H); LRMS APCI m/z 262[M+NH₄]⁺

Preparation 68 3,5-Difluoro-2-methylphenol

Sodium borohydride (2.28 g, 60.40 mmol) was added to a solution of theproduct of preparation 67 (2.85 g, 12.08 mmol) in 1,2-dimethoxyethane(25 mL) and the mixture was heated at 45° C. for 18 hours. The reactionmixture was then cooled with an ice/acetone bath and quenched withsaturated ammonium chloride solution. The mixture was extracted withdiethyl ether (2×20 mL) and the combined organic solution was washedwith saturated ammonium chloride solution, dried over magnesium sulfateand concentrated in vacuo to afford the title compound in 75% yield, 1.3g. ¹H NMR (400 MHz, CDCl₃) δ: 2.10 (s, 3H), 5.10-5.20 (brs, 1H),6.35-6.45 (m, 2H).

Preparation 69 2-Hydroxyacetohydrazide

Hydrazine monohydrate (1.08 g, 22.2 mmol) was added to a solution ofmethyl glycolate (0.84 mL, 11.1 mmol) in methanol (10 mL) and themixture was heated under reflux for 2 hours and stirred at roomtemperature for 72 hours. The reaction mixture was then concentrated invacuo to afford the title compound as a white solid in quantitativeyield. ¹H NMR (400 MHz, CDCl₃) δ: 4.04 (s, 2H)

Preparation 70 4-Hydroxy-3-methylbenzonitrile

A mixture of 4-hydroxy-3-methylbenzaldehyde (530 mg, 3.91 mmol) andhydroxyl ammonium chloride (406 mg, 5.81 mmol) in acetic acid (5 mL) washeated under reflux for 90 minutes. The cooled reaction mixture was thendiluted with diethyl ether (30 mL) and washed with water (30 mL). Thecombined organic solution was washed with brine, dried over magnesiumsulfate, concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol,100:0 to 97.5:2.5, to afford the title compound as a pale yellow oil in66% yield, 345 mg.

¹H NMR (400 MHz, CDCl₃) δ: 2.25 (s, 3H), 6.84 (d, 1H), 7.37 (d, 1H),7.40 (s, 1H)

Preparation 71 3-Chloro-4-hydroxybenzonitrile

The title compound was prepared from 3-chloro-4-hydroxybenzaldehyde andhydroxyl ammonium chloride, using the same method as that described forpreparation 70. The title compound was purified by column chromatographyon silica gel, eluting with pentane:ethyl acetate, 100:0 to 90:10, toafford the title compound as a white solid in 76% yield.

¹H NMR (400 MHz, CDCl₃) δ: 7.10 (d, 1H), 7.52 (d, 1H), 7.66 (s, 1H)

Preparation 72 2-Chloro-3-hydroxybenzonitrile

A mixture of 2-chloro-3-hydroxybenzaldehyde [(2 g, 12.8 mmol) WO2005007633, p 34] and hydroxyl ammonium chloride (1.33 g, 19.6 mmol) inacetic acid (20 mL) was heated under reflux for 2 hours. The reactionmixture was then cooled to room temperature and partitioned betweendiethyl ether and water. The organic layer was separated, washed withbrine, dried over magnesium sulfate and concentrated in vacuo to give awhite solid. The solid was then dissolved in ethyl acetate washed withwater and brine, dried over magnesium sulfate and concentrated in vacuoto afford the title compound as a solid in quantitative yield. ¹H NMR(400 MHz, CD₃OD) δ: 7.18 (d, 1H), 7.26 (m, 2H)

Preparation 73 3-Fluoro-2-(trifluoromethyl)phenol

A solution of 3-fluoro-2-(trifluoromethyl)bromobenzene (1 g, 4.1 mmol)in tetrahydrofuran (25 mL) was added dropwise to ^(n)butyl lithium (2.5Min hexanes, 3.2 mL, 8 mmol), at −78° C., and the mixture was stirred atthis temperature for 30 minutes. Trimethyl borate (1.84 mL, 16.4 mmol)was added and the reaction mixture was stirred at −78° C. for a further30 minutes and at room temperature for 18 hours. 2M sodium hydroxidesolution (4 mL) and 35% hydrogen peroxide solution (2 mL) were thenadded and the mixture was heated under reflux for 3 hours. The reactionmixture was cooled to room temperature and diluted with diethyl ether(100 mL). The aqueous layer was separated and the organic solution waswashed with 2M sodium hydroxide solution. The combined basic washingswere acidified with 2M hydrochloric acid, extracted with diethyl ether(2×50 mL) and the organic solution was concentrated in vacuo to affordthe title compound as a yellow oil in 40% yield, 300 mg. ¹H NMR (400MHz, CD₃OD) δ: 6.64 (m, 1H), 6.75 (d, 1H), 7.36 (q, 1H)

Preparation 74 3-Hydroxy-2-methylbenzonitrile

A solution of 3-methoxy-2-methylbenzonitrile [(1 g, 6.79 mmol) U.S. Pat.No. 5,965,766, p 6] and tetra ^(n)butyl ammonium iodide (4.12 g, 17mmol) in dichloromethane (15 mL) was cooled to −78° C. and purged withnitrogen. Boron trichloride (1M in dichloromethane, 17 mL, 17 mmol) wasadded dropwise and the mixture was stirred for 15 minutes at −78° C. andat room temperature for 3 hours. The reaction mixture was quenched withwater, stirred for 30 minutes and concentrated in vacuo. The aqueousresidue was extracted with diethyl ether and the organic solution waswashed with water (×5), dried over magnesium sulfate and concentrated invacuo to afford the title compound as a brown solid in 91% yield, 826mg. ¹H NMR (400 MHz, CDCl₃) δ: 2.20 (s, 3H), 7.10 (m, 1H), 7.20 (d, 1H),10.10 (s, 1H); LRMS APCI m/z 132 [M−H]⁻

Preparation 75 3-Hydroxy-2-methylbenzamide

Oxalyl chloride (4.19 ml, 48 mmol) was added to an ice-cold solution of3-hydroxy-2-methylbenzoic acid (3.62 g, 24 mmol) in dichloromethane (30mL). N,N-dimethylformamide (2 mL) was then added and the mixture wasstirred at room temperature for 18 hours. The reaction mixture wasconcentrated in vacuo and the residue was concentrated in vacuo threetimes from toluene. The residue was then suspended in tetrahydrofuran(10 mL), added to ice-cold 0.88 ammonia solution (10 mL) and stirred for2.5 hours, allowing the temperature to rise to ambient. The reactionmixture was then extracted with ethyl acetate, dried over magnesiumsulfate and concentrated in vacuo and the residue was concentrated invacuo from acetone and triturated with diethyl ether to afford the titlecompound as a solid in 45% yield. LRMS APCI m/z 152 [M+H]⁺.

Preparation 76 3-Hydroxy-N,N,2-trimethylbenzamide

The title compound was prepared from 3-hydroxy-2-methylbenzoic acid anddimethylamine, using the same method as that described for preparation75, as a solid in 42% yield. ¹H NMR (400 MHz, CDCl₃) δ: 1.95 (s, 3H),2.70 (s, 3H), 2.95 (s, 3H), 6.55 (d, 1H), 6.80 (d, 1H), 7.00 (m, 1H),9.50 (s, 1H); LRMS APCI m/z 180 [M+H]⁺

Preparation 77 2-(Methoxymethyl)phenol

A solution of 2-hydoxybenzyl alcohol (5 g, 40 mmol) in methanol (25 mL)was heated in a sealed vessel at 150° C. for 4 hours. The reactionmixture was then concentrated in vacuo and the residue was purified byfractional distillation (90° C./10 mm Hg) to afford the title compoundas a colourless liquid in 58% yield, 3.22 g. LRMS APCI m/z 137 [M−H]⁻

Preparation 78 3-(2-Chloro-4-fluorophenoxy)-1-(diphenylmethyl)azetidine

A mixture of 1-(diphenylmethyl)-3-azetidinyl methanesulfonate (363.8 g,1.15 mol), potassium carbonate (330 g, 2.38 mol) and2-chloro-4-fluorophenol (140 g, 0.96 mol) in acetonitrile (2.5 L) washeated under reflux for 4.5 hours. The cooled reaction mixture was thenconcentrated in vacuo and the residue was partitioned between ethylacetate (1 L) and water (500 mL). The organic layer was separated, driedover sodium sulfate concentrated in vacuo and the residue was trituratedwith ethyl acetate/pentane/dichloromethane, 90:10:1, to afford the titlecompound as a white solid in quantitative yield, 350 g. ¹H NMR (400 MHz,CDCl₃) δ: 3.19 (m, 2H), 3.75 (m, 2H), 4.45 (m, 1H), 4.78 (m, 1H), 6.60(m, 1H), 6.83 (m, 1H), 7.14 (m, 1H), 7.18-7.50 (m, 10H)

Preparation 79 3-(2-Chloro-4-fluorophenoxy)azetidine hydrochloride

A solution of the product of preparation 78 (5 g, 13.59 mmol) and1,8-bis(dimethylamino)naphthalene (2.91 g, 13.59 mmol) in dichloroethane(50 mL) was treated with chloroethylchloroformate (4.08 g, 28.54 mmol)and the mixture was then heated under reflux for 2 hours. The reactionmixture was cooled to room temperature, diluted with dichloromethane (60mL), washed with 2N hydrochloric acid (2×30 mL), dried over sodiumsulfate and concentrated in vacuo. The residue was then azeotroped withtoluene and dichloromethane, triturated with diethyl ether and purifiedby HPLC using a Phenomenex Luna C18 system, eluting withwater/acetonitrile/trifluoroacetic acid (5:95:0.1):acetonitrile, 95:5 to5:95, to afford the title compound in 52% yield, 1.69 g. ¹H NMR (400MHz, CDCl₃) δ: 4.22 (m, 2H), 4.58 (m, 2H), 5.18 (m, 1H), 6.92 (m, 1H),7.04 (m, 1H), 7.30 (m, 1H); LRMS ESI m/z 202 [M+H]⁺.

Preparation 803-(2-Chloro-4-fluorophenoxy)-N-(6-methoxypyridin-3-yl)azetidine-1-carbothioamide

N-methylmorpholine (16.6 mL, 150.8 mmol) and5-isothiocyanato-2-methoxypyridine [(20.9 g, 125.7 mmol), J. Org. Chem.(1980), 45, 4219] were added portionwise to a ice-cooled suspension ofthe product of preparation 79 [(29.93 g, 125.7 mmol) in tetrahydrofuran(150 mL) and the mixture was stirred for 1 hour at room temperature. Thereaction mixture was concentrated in vacuo and the residue wasre-crystallised from water. The resulting solid was filtered, washingthrough with water and diethyl ether, and dried under vacuum, at 45° C.,for 18 hours to afford the title compound as a solid in 74% yield, 34 g.

LRMS APCI m/z 368 [M+H]⁺.

Preparation 81 Methyl3-(2-chloro-4-fluorophenoxy)-N-(6-methoxypyridin-3-yl)azetidine-1-carbimidothioate

The title compound was prepared from the product of preparation 80 andpotassium tert-butoxide, using the same method as that described forpreparation 3, in quantitative yield. LRMS APCI m/z 382 [M+H]⁺.

Preparation 821-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]azetidin-3-ol

A mixture of the product of preparation 4 (1 g, 2.95 mmol) and 2M sodiumhydroxide solution (10 mL) in ethanol (20 mL) was heated under refluxfor 24 hours. The reaction mixture was then cooled to room temperature,acidified to pH6 with hydrochloric acid and extracted withdichloromethane. The organic solution was concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 100:0 to 50:50, to afford the titlecompound as a brown oil in 26% yield, 200 mg. ¹H NMR (400 MHz, CDCl₃) δ:2.17 (s, 3H), 3.80 (m, 2H), 3.95 (m, 2H), 4.03 (s, 3H), 4.57 (m, 1H),6.88 (d, 1H), 7.52 (dd, 1H), 8.11 (d, 1H); LRMS ESI m/z 262 [M+H]⁺.

Preparation 83 3-Methoxy-4-[(3R)-pyrrolidin-3-yloxy]benzonitrile

4-Hydroxy-3-methoxybenzonitrile (12 g, 80.2 mmol) and triphenylphosphine(21 g, 80.2 mmol) were added portionwise to an ice-cold solution oftert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (15 g, 80.2 mmol) intetrahydrofuran (225 mL). A solution of diisopropyl azodicarboxylate(16.2 g, 80.2 mmol) in tetrahydrofuran (100 mL) was then added dropwiseand the mixture was stirred at room temperature for 18 hours. Thereaction mixture was then concentrated in vacuo and the residue wastreated with hydrochloric acid (4M in dioxane, 250 mL). The mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate and water. The organic layer was separated and washed with water(100 mL), and the combined aqueous solution was washed with ethylacetate (2×150 mL), basified to pH10 with solid potassium carbonate andextracted with ethyl acetate (2×250 mL). The combined organic solutionwas washed with brine (100 mL), dried over magnesium sulfate andconcentrated in vacuo to afford the title compound as a cream solid in67% yield, 11.8 g. LRMS ESI m/z 219 [M+H]⁺.

Preparation 84 (3R)-3-(2-Chlorophenoxy)pyrrolidine hydrochloride

Diisopropyl azodicarboxylate (21 mL, 107 mmol) and4-hydroxy-3-chlorophenol (11.1 mL, 107 mmol) were added portionwise toan ice-cold solution of tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate (20 g, 107 mmol) andtriphenylphosphine (28.1 g, 107 mmol) in tetrahydrofuran (320 mL) andthe mixture was stirred at room temperature for 18 hours. The reactionmixture was then concentrated in vacuo and the residue was treated withhydrochloric acid (4M in dioxane, 250 mL). The mixture was concentratedin vacuo and the residue was partitioned between ethyl acetate (400 mL)and water (400 mL). The organic layer was separated and washed withwater (100 mL), and the combined aqueous solution was washed with ethylacetate (2×300 mL), basified to pH9 with solid potassium carbonate andextracted with ethyl acetate (2×400 mL). The combined organic solutionwas then washed with water (3×300 mL), dried over magnesium sulfate andconcentrated in vacuo. The residual oil was dissolved in diethyl ether(60 mL), treated dropwise with hydrochloric acid (4M in dioxane, 25 mL)and the resulting precipitate was filtered off, washing through withdiethyl ether, and dried to afford the title compound as a white solidin 55% yield, 13.69 g. LRMS APCI m/z 198 [M+H]⁺.

Preparation 85 (3R)-3-(2-methoxyphenoxy)pyrrolidine hydrochloride

The title compound was prepared from tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate and 2-methoxyphenol, using thesame method as that described for preparation 84, as a white solid in45% yield. Microanalysis. found (%) C (57.43), H (7.05), N (6.08);C₁₁H₁₅NO₂ requires. (%) C (57.50), H (6.96), N (6.09)

Preparation 86 (3R)-3-(2-Methylphenoxy)pyrrolidine hydrochloride

The title compound was prepared from tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate and o-Cresol, using the samemethod as that described for preparation 84, as a pale pink solid in 54%yield. LRMS APCI m/z 178 [M+H]⁺.

Preparation 87 2-[(3R)-pyrrolidin-3-yloxy]benzonitrile maleate

2-Hydroxybenzonitrile (9.5 g, 80.2 mmol) and triphenylphosphine (21 g,80.2 mmol) were added portionwise to an ice-cold solution of tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate (15 g, 80.2 mmol) intetrahydrofuran (225 mL). A solution of diisopropyl azodicarboxylate(16.2 g, 80.2 mmol) in tetrahydrofuran (100 mL) was then added dropwiseand the mixture was stirred at room temperature for 18 hours. Thereaction mixture was then concentrated in vacuo and the residue wastreated with hydrochloric acid (4M in dioxane, 250 mL). The mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate and water. The organic layer was separated and washed water (100mL), and the combined aqueous solution was washed with ethyl acetate(2×150 mL), basified to pH10 with solid potassium carbonate andextracted with ethyl acetate (2×250 mL). The combined organic solutionwas washed with brine (100 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue was diluted with ethyl acetate andtreated with a solution of maleic acid (6.5 g) in ethyl acetate (200 mL)and the mixture was stirred at room temperature for 30 minutes. Theresulting precipitate was then filtered off, washing through with ethylacetate, and dried to afford the title compound as a cream solid in 49%yield, 12 g.

LRMS ESI m/z 189 [M+H]⁺.

Preparation 88 4-[(3R)-Pyrrolidin-3-yloxy]benzonitrile maleate

4-Hydroxybenzonitrile (9.5 g, 80.2 mmol) and triphenylphosphine (21 g,80.2 mmol) were added portionwise to an ice-cold solution of tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate (15 g, 80.2 mmol) intetrahydrofuran (225 mL). A solution of diisopropyl azodicarboxylate(16.2 g, 80.2 mmol) in tetrahydrofuran (100 mL) was then added dropwiseand the mixture was stirred at room temperature for 18 hours. Thereaction mixture was then concentrated in vacuo and the residue wastreated with hydrochloric acid (4M in dioxane, 250 mL). The mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate and water. The organic layer was separated and washed water (100mL), and the combined aqueous solution was washed with ethyl acetate(2×150 mL), basified to pH10 with solid potassium carbonate andextracted with ethyl acetate (2×250 mL). The combined organic solutionwas washed with brine (100 mL), dried over magnesium sulfate,concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol:0.88ammonia, 97:3:1 to 90:10:1. The appropriate franctions were evaporatedunder reduced pressure and the residue was diluted with ethyl acetateand treated with a solution of maleic acid (5 g) in ethyl acetate (140mL). The resulting precipitate was then filtered off, washing throughwith ethyl acetate, and dried to afford the title compound as a creamsolid in 65% yield, 9.87 g. LRMS ESI m/z 189 [M+H]⁺.

Preparation 89 (3R)-3-(4-Fluorophenoxy)pyrrolidine

Diethyl azodicarboxylate (60.5 mL, 384 mmol) was added to an ice-cooledmixture of (S)-(−)-1-benzyl-3-pyrrolidinol (56.72 g, 320 mmol),4-fluorophenol (39.45 g, 352 mmol) and triphenyl phosphine (100.7 g, 384mmol) in tetrahydrofuran (500 mL) and the mixture was stirred for 18hours, allowing the temperature to rise to ambient. The reaction mixturewas then concentrated in vacuo and the residue was taken up inpentane:dichloromethane, 90:10. The resulting precipitate was filteredoff and the filtrate was concentrated in vacuo. The residue was thenpurified by column chromatography on silica gel, eluting withdichloromethane. The appropriate fractions were evaporated under reducedpressure and a portion of the residue (5 g) was dissolved in methanol(100 mL). 10% Pd/C (0.5 g) and ammonium formate (5.8 g, 92 mmol) wereadded and the mixture was stirred at room temperature for 3 hours. Themixture was then filtered through Arbocel® and the filtrate wasconcentrated in vacuo purified by column chromatography on silica gel,eluting with dichloromethane;methanol, 0.88 ammonia, 95:5:0.5 to90:10:1, to afford the title compound as a colourless oil. ¹H NMR (400MHz, DMSO-d₆) δ: 2.03 (m, 2H), 3.10-3.29 (m, 3H), 3.36 (m, 1H), 5.01 (m,1H), 6.96 (m, 2H), 7.08 (m, 2H).

Preparation 90 (3S)-3-(2-Methoxyphenoxy)pyrrolidine hydrochloride

The title compound was prepared from tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate and 2-methoxyphenol, using thesame method as that described for preparation 84, as a pale pink solidin 40% yield. LCMS APCI m/z 194 [M+H]⁺.

Preparation 91 (3S)-3-(2-Chlorophenoxy)pyrrolidine hydrochloride

The title compound was prepared from tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate and 2-chlorophenol, using thesame method as that described for preparation 84, as a pale pink solidin 54% yield. LCMS APCI m/z 198 [M+H]⁺

Preparation 92 (3S)-3-(2-Methylphenoxy)pyrrolidine hydrochloride

The title compound was prepared from tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate and 2-methylphenol, using thesame method as that described for preparation 84, as a white solid in40% yield. LCMS APCI m/z 178 [M+H]⁺.

Preparation 93(3S)-3-Hydroxy-N-(6-methoxypyridin-3-yl)pyrrolidine-1-carbothioamide

The title compound was prepared from (S)-3-hydroxypyrrolidine and5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219),using the same method as that described for preparation 35, in 99%yield. ¹H NMR (400 MHz, CD₃OD) δ: 1.91-2.22 (m, 2H), 3.69-3.81 (m, 4H),3.88 (s, 3H), 4.40-4.52 (m, 1H), 6.78 (d, 1H), 7.69 (dd, 1H), 8.00 (m,1H); LCMS m/z 254 [M+H]⁺.

Preparations 94 to 100

The following compounds, of the general formula shown below, wereprepared using the same method to that described for preparation 35,using the products of preparations 83-89 and5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219).

No. R¹ Data (LRMS and/or ¹H NMR) Yield 94

APCI m/z 385 [M + H]⁺ 95% 95

δ: 2.30(m, 1H), 2.45(m, 1H), 3.87-4.20(m, 7H), 5.05(m, 1H), 6.80(m, 2H),6.95(m, 2H), 7.25(m, 1H), 7.40(d, 1H), 7.76(dd, 1H), 8.05(d, 1H); APCIm/z 364 [M + H]⁺ 67% 96

APCI m/z 360 [M + H]⁺ 93% 97

δ: 2.20(s, 3H), 2.30(m, 1H), 2.45(m, 1H), 3.80-4.00(m, 5H), 4.05(m, 2H),5.08(m, 1H), 6.78(m, 3H), 6.90(d, 1H), 7.15(m, 1H), 7.70(dd, 1H),8.05(d, 1H); APCI m/z 344 [M + H]⁺ 85% 98

APCI m/z 355 [M + H]⁺ 97% 99

APCI m/z 355 [M + H]⁺ 59% 100 

APCI m/z 348 [M + H]⁺ 72% NMR spectra were run at 400 MHz in CDCl₃

Preparation 101(3S)-3-(2-Methoxyphenoxy)-N-(6-methoxypyridin-3-yl)pyrrolidine-1-carbothioamide

The title compound was prepared from the product of preparation 90 and5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219),using the same method as that described for preparation 35, in 90%yield.

LRMS APCI m/z 360 [M+H]⁺.

Preparation 102 Methyl(3S)-3-hydroxy-N-(6-methoxypyridin-3-yl)pyrrolidine-1-carbimidothioate

The title compound was prepared from the product of preparation 93 andmethyl p-toluenesulfonate, using the same method as that described forpreparation 3. The crude compound was re-crystallised from diethylether/cyclohexane to afford the desired product as a solid in 94% yield.¹H NMR (400 MHz, CD₃OD) δ: 1.91-2.20 (m, 2H), 2.01 (s, 3H), 3.58 (m,1H), 3.63-3.75 (m, 3H), 3.83 (s, 3H), 4.40 (m, 1H), 6.77 (d, 1H), 7.34(dd, 1H), 7.68 (m, 1H); LCMS m/z 268 [M+H]⁺

Preparations 103 to 109

The following compounds, of the general formula shown below, wereprepared using the same method to that described for preparation 3,using the products of preparations 94 to 100 and methylp-toluenesulfonate.

No. R¹ Data (LRMS and/or ¹H NMR) Yield 103

LRMS APCI m/z 399 [M + H]⁺ 79% 104

δ: 2.00(s, 3H), 2.20(m, 1H), 2.30(m, 1H), 3.87- 4.20(m, 7H), 5.00(m,1H), 6.65(d, 1H), 6.95(m, 2H), 7.25(m, 2H), 7.40(dd, 1H), 7.80(d, 1H);APCI m/z 378 [M + H]⁺ 97% 105

APCI m/z 374 [M + H]⁺ 65% 106

δ: 2.00(s, 3H), 2.20(m, 4H), 2.28(m, 1H), 3.80(m, 4H), 3.90(s, 3H),4.98(m, 1H), 6.68(d, 1H), 6.80(d, 1H), 6.90(m, 1H), 7.15(m, 2H), 7.25(m,1H), 7.80(d, 1H); APCI m/z 358 [M + H]⁺ 92% 107

APCI m/z 369 [M + H]⁺ 92% 108

APCI m/z 369 [M + H]⁺ 98% 109

APCI m/z 362 [M + H]⁺ 79% NMR spectra were run at 400 MHz in CDCl₃

Preparation 110(3S)-1-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]pyrrolidin-3-ol

The title compound was prepared from the product of preparation 102 andacetylhydrazide, using the same method as that described for preparation4. The crude compound was triturated with pentane to afford the desiredproduct in 44% yield. ¹H NMR (400 MHz, CD₃OD) δ: 1.78-1.87 (m, 1H),1.90-2.02 (m, 1H), 2.15 (s, 3H), 3.03 (m, 1H), 3.18-3.30 (m, 3H), 4.01(s, 3H), 4.33 (m, 1H), 6.98 (d, 1H), 7.78 (dd, 1H), 8.23 (m, 1H); LCMSm/z 276 [M+H]⁺.

Preparation 111 2-(Benzyloxy)-6-fluoropyridine

Benzylalcohol (1.88 g, 17.38 mmol) was added to a suspension of sodiumhydride (60% dispersion in mineral oil, 458 mg, 19.11 mmol) intetrahydrofuran (15 mL) and the mixture was heated to 50° C. for 45minutes. The reaction mixture was then cooled to room temperature, asolution of 2,6-difluoropyridine (2 g, 17.38 mmol) in tetrahydrofuran (4mL) was added dropwise and the mixture was stirred at room temperaturefor 45 minutes. The reaction mixture was then diluted with ethylacetate, concentrated in vacuo and the residue was partitioned betweenethyl acetate (50 mL) and water (20 mL). The organic layer wasseparated, washed with brine (20 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue was then concentrated in vacuo fromdichloromethane to afford the title compound as a clear oil in 98%yield, 3.48 g. LRMS APCI m/z 204 [M+H]⁺.

Preparation 112 tert-Butyl4-{[6-(benzyloxy)pyridin-2-yl]oxy}piperidine-1-carboxylate

A solution of 1-boc-4-hydroxypiperidine (501 mg, 2.49 mmol) intetrahydrofuran (10 mL) was added dropwise to a suspension of sodiumhydride (60% dispersion in mineral oil, 65 mg, 2.74 mmol) and themixture was heated at 55° C. for 1 hour. The reaction mixture was thencooled to room temperature, a solution of the product of preparation 111(506 mg, 2.49 mmol) in tetrahydrofuran (3 mL) was added dropwise and themixture was stirred at room temperature for 45 minutes and at 70° C. for18 hours. The cooled reaction mixture was partitioned between ethylacetate (20 mL) and water (10 mL), the organic layer was separated,washed with brine, dried over magnesium sulfate and concentrated invacuo. Purification of the residue by column chromatography on silicagel, eluting with pentane:ethyl acetate, 100:0 to 90:10, afforded thetitle compound as a white solid in 49% yield, 470 mg. LRMS APCI m/z 385[M+H]⁺.

Preparation 113 tert-Butyl4-[(6-oxo-1,6-dihydropyridin-2-yl)oxy]piperidine-1-carboxylate

The title compound was prepared from the product of preparation 112,using the same method as that described for preparation 17, in 96%yield.

LRMS APCI m/z 295 [M+H]⁺.

Preparation 114 tert-Butyl4-[(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)oxy]piperidine-1-carboxylate

Sodium hydride (60% dispersion in mineral oil, 27 mg, 1.12 mmol) wasadded to a solution of the product of preparation 113 (276 mg, 0.93mmol) in tetrahydrofuran (4 mL) and the mixture was stirred for 30minutes at room temperature. Methyl p-toluenesulfonate (192 mg, 1.03mmol) was then added and the mixture was stirred for a 18 hours at roomtemperature. Further methyl p-toluenesulfonate (87.3 mg, 0.47 mmol) wasadded and the mixture was stirred at room temperature for 72 hours. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between ethyl acetate (10 mL) and water (5 mL). The organiclayer was separated, washed with water and brine, dried over magnesiumsulfate and concentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with dichloromethane:methanol,100:0 to 97:3 afforded the title compound in 59% yield, 170 mg. LRMSAPCI m/z 309 [M+H]⁺.

Preparation 115 1-Methyl-6-(piperidin-4-yloxy)pyridin-2(1H)-onehydrochloride

The title compound was prepared from the product of preparation 114,using the same method as that described for preparation 50, as a solidin quantitative yield.

LRMS APCI m/z 209 [M+H]⁺.

Preparation 116N-(6-Methoxypyridin-3-yl)-4-[(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)oxy]piperidine-1-carbothioamide

The title compound was prepared from the product of preparation 115 and5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219),using the same method as that described for preparation 35, in 50%yield.

LRMS APCI m/z 375 [M+H]⁺.

Preparation 1171-[5-Methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-3-ol

The title compound was prepared from the product of preparation 102 andthe compound of preparation 5, using the same method as that describedfor preparation 4. The crude compound was triturated with pentane toafford the desired product in 58% yield. LCMS m/z 306 [M+H]⁺.

Preparation 1181-[5-Methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-azetidin-3-ol

The title compound was prepared from the compound of preparation 6,using the same method as that described for preparation 82, in 68%yield.

LRMS ESI m/z 292 [M+H]⁺

Example 15-{3-[3-(4-Fluorophenoxy)azetidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine

Sodium hydride (60% dispersion in mineral oil, 12 mg, 0.3 mmol) wasadded to a solution of 4-fluorophenol (33 mg, 0.3 mmol) inN,N-dimethylformamide (2 mL) and the mixture was stirred at roomtemperature until effervescence had ceased. The product of preparation 4(50 mg, 0.15 mmol) was then added and the mixture was heated at 100° C.for 40 hours. The cooled reaction mixture was then partitioned betweenwater and dichloromethane and the organic layer was separated andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel, eluting with dichloromethane:methanol, 100:0 to 95:5, toafford the title compound in 41% yield, 21.8 mg. ¹H NMR (400 MHz, CDCl₃)δ: 2.18 (s, 3H), 3.91 (m, 2H), 3.99 (s, 3H), 4.12 (m, 2H), 4.84 (m, 1H),6.63 (m, 2H), 6.91 (m, 3H), 7.50 (dd, 1H), 8.10 (d, 1H); LRMS ESI m/z356 [M+H]⁺.

Examples 2 to 31

The following compounds, of the general formula shown below, wereprepared using the same method to that described for example 1, usingeither the product of preparation 4 (examples 2-14) or the product ofpreparation 6 (15-31) and commercially available phenols or compoundsknown in the literature as outlined below.

No. X′_(n) R² Data (LRMS* and/or ¹H NMR) Yield 2 3-OCH₃ H δ: 2.18(s,3H), 3.76(s, 3H), 3.91(m, 2H), 27% 3.99(s, 3H), 4.18(m, 2H), 4.88(m,1H), 6.23(m, 2H), 6.52(dd, 1H), 6.88(d, 1H), 7.16(m, 1H), 7.54(dd, 1H),8.13(d, 1H); ESI m/z 367 [M + H]⁺ 3 2-CH₃, 4-CN H δ: 1.77(s, 3H),2.10(s, 3H), 3.96(m, 2H), 40% 4.00(s, 3H), 4.16(m, 2H), 4.95(m, 1H),6.40(d, 1H), 6.90(m, 1H), 7.39(m, 2H), 7.48(dd, 1H), 8.12(d, 1H); ESIm/z 376 [M + H]⁺ 4 2-CH₃, 4-F H δ: 2.17(s, 3H), 2.20(s, 3H), 3.92(m,2H), 45% 3.99(s, 3H), 4.08(m, 2H), 4.83(m, 1H), 6.30(d, 1H), 6.74(m,1H), 6.85(dd, 1H), 6.89(d, 1H), 7.49(dd, 1H), 8.12(d, 1H); ESI m/z 370[M + H]⁺ 5 4-CH₃ H δ: 2.18(s, 3H), 2.24(s, 3H), 3.93(m, 2H), 41% 4.00(s,3H), 4.11(m, 2H), 4.86(m, 1H), 6.58(d, 2H), 6.89(d, 1H), 7.03(d, 2H),7.50(dd, 1H), 8.10(d, 1H); ESI m/z 352 [M + H]⁺ 6 2-CH₃, 5-F H δ:2.16(8, 3H), 2.21(s, 3H), 3.95(m, 2H), 35% 4.02(s, 3H), 4.14(m, 2H),4.84(m, 1H), 6.11(d, 1H), 6.57(m, 1H), 6.90(dd, 1H), 7.04(d, 1H),7.49(dd, 1H), 8.12(d, 1H); ESI m/z 370 [M + H]⁺ 7 4-Cl H δ: 2.19(s, 3H),3.93(m, 2H), 4.00(s, 3H), 23% 4.12(m, 2H), 4.84(m, 1H), 6.60(d, 2H),6.87(d, 1H), 7.19(d, 2H), 7.48(dd, 1H), 8.10(d, 1H); ESI m/z 372 [M +H]⁺ 8 3-F H ESI m/z 356 [M + H]⁺ 35% 9 3-F, 5-F H ESI m/z 374 [M + H]⁺10% 10 2-Cl H δ: 2.20(s, 3H), 4.00(m, 5H), 4.16(m, 2H), 32% 4.94(m, 1H),6.53(d, 1H), 6.90(m, 2H), 7.14(m, 1H), 7.35(d, 1H), 7.52(dd, 1H),8.11(d, 1H); ESI m/z 372 [M + H]⁺ 11 2-CN H ESI m/z 363 [M + H]⁺ 31% 122-Cl, 4-F H δ: 2.20(s, 3H), 4.02(m, 5H), 4.14(m, 2H), 20% 4.88(m, 1H),6.53(d, 1H), 6.88(m, 2H), 7.11(m, 1H), 7.52(dd, 1H), 8.13(d, 1H); ESIm/z 390 [M + H]⁺ 13 2-F, 6-F H ESI m/z 374 [M + H]⁺ 27% 14 2-F, 4-F HESI m/z 374 [M + H]⁺ 54% 15 3-F, 4-F OCH₃ δ: 3.27(s, 3H), 3.94(m, 2H),4.01(s, 3H), 48% 4.18(m, 2H), 4.32(s, 2H), 4.85(m, 1H), 6.38(m, 1H),6.54(m, 1H), 6.85(d, 1H), 7.03(m, 1H), 7.59 (dd, 1H), 8.10(d, 1H); LCMSm/z 368 [M + H]⁺ 16 3-CH₃ OCH₃ δ: 2.17(s, 3H), 3.30(s, 3H), 3.97(m, 2H),53% 4.00(s, 3H), 4.18(m, 2H), 4.32(s, 2H), 4.90(m, 1H), 6.45(m, 2H),6.52(dd, 1H), 6.78(d, 1H), 7.14(m, 1H), 7.59(dd, 1H), 8.21(d, 1H); ESIm/z 382 [M + H]⁺ 17 3-OCH₃ OCH₃ δ: 3.28(s, 3H), 3.76(s, 3H), 3.94(m,2H), 54% 3.99(s, 3H), 4.16(m, 2H), 4.31(s, 2H), 4.90(m, 1H), 6.23(m,2H), 6.53(dd, 1H), 6.85(d, 1H), 7.14(m, 1H), 7.58(dd, 1H), 8.19(d, 1H);ESI m/z 398 [M + H]⁺ 18 3-Cl OCH₃ δ: 3.27(s, 3H), 3.95(m, 2H), 3.99(s,3H), 38% 4.22(m, 2H), 4.31(s, 2H), 4.92(m, 1H), 6.56(dd, 1H), 6.68(m,1H), 6.86(d, 1H), 6.95(dd, 1H), 7.18(m, 1H), 7.64(dd, 1H), 8.02(d, 1H);ESI m/z 402 [M + H]⁺ 19 3-CF₃ OCH₃ δ: 3.30(s, 3H), 3.97(m, 2H), 3.99(s,3H), 57% 4.20(m, 2H), 4.32(m, 2H), 4.96(m, 1H), 6.85(m, 2H), 6.94(s,1H), 7.25(m, 1H), 7.37(m, 1H), 7.60(dd, 1H) 8.22(d, 1H); ESI m/z 436[M + H]⁺ 20 3-F OCH₃ δ: 3.32(s, 3H), 3.97(m, 2H), 4.02(s, 3H), 49%4.18(m, 2H), 4.34(m, 2H), 4.95(m, 1H), 6.42(m, 1H), 6.44(m, 1H), 6.68(m,1H), 6.86(d, 1H), 7.19(m, 1H), 7.60(dd, 1H), 8.21(d, 1H); ESI m/z 408[M + Na]⁺ 21 4-F OCH₃ δ: 3.29(s, 3H), 3.96(m, 2H), 3.99(s, 3H), 51%4.14(m, 2H), 4.32(m, 2H), 4.86(m, 1H), 6.62(m, 2H), 6.85(d, 1H), 6.92(m,2H), 7.59(dd, 1H), 8.19(d, 1H); ESI m/z 386 [M + H]⁺ 22 2-Cl OCH₃ δ:3.30(s, 3H), 3.99(s, 3H), 4.05(dd, 2H), 48% 4.18(dd, 2H), 4.32(s, 2H),4.95(m, 1H), 6.52(m, 1H), 6.86(d, 1H), 6.92(m, 1H), 7.15(m, 1H),7.36(dd, 1H), 7.60(dd, 1H), 8.21(d, 1H); APCI m/z 402/404 [M + H]⁺ 232-CN OCH₃ APCI m/z 393 [M + H]⁺ 70% 24 2-F, 4-F OCH₃ APCI m/z 404 [M +H]⁺ 53% 25 2-Cl, 4-F OCH₃ δ: 3.29(s, 3H), 3.99(s, 3H), 4.05(dd, 2H), 28%4.24(dd, 2H), 4.31(s, 2H), 4.92(m, 1H), 6.50(m, 1H), 6.77(m, 1H),6.87(d, 1H), 7.12(dd, 1H), 7.65(dd, 1H), 8.22(d, 1H); APCI m/z 420/422[M + H]⁺ 26 2-F, 6-F OCH₃ APCI m/z 404 [M + H]⁺ 83% 27 2-CH₃, 5-Cl, OCH₃δ: 2.13(s, 3H), 3.29(s, 3H), 3.99(dd, 2H), 57% 4.00(s, 3H), 4.23(dd,2H), 4.31(s, 2H), 4.91(m, 1H), 6.34(d, 1H), 6.84(dd, 1H), 6.88(d, 1H),7.03(d, 1H), 7.64(d, 1H), 8.22(d, 1H); APCI m/z 416/418 [M + H]⁺ 282-CH₃, 3-CH₃ OCH₃ δ: 2.10(s, 3H), 2.24(s, 3H), 3.29(s, 3H), 70%3.99-4.01(m, 5H), 4.19(dd, 2H), 4.31(s, 2H), 4.90(m, 1H), 6.23(d, 1H),6.78(d, 1H), 6.86(d, 1H), 6.96(m, 1H), 7.61(dd, 1H), 8.20(d, 1H); APCIm/z 396 [M + H]⁺ 29 2-CH₃, 6-CH₃ OCH₃ δ: 2.15(s, 6H), 3.29(s, 3H),4.00(s, 3H), 45% 4.06(dd, 2H), 4.13(dd, 2H), 4.31(s, 2H), 4.57(m, 1H),6.85-6.92(m, 2H), 6.95-6.99(m, 2H), 7.63(dd, 1H), 8.22(d, 1H); APCI m/z396 [M + H]⁺ 30 2-CH₂CH₃ OCH₃ δ: 1.16(t, 3H), 2.60(q, 2H), 3.29(s, 3H),3.98- 70% 4.00(m, 5H), 4.22(dd, 2H), 4.31(s, 2H), 4.95(m, 1H), 6.38(d,1H), 6.86(d, 1H), 6.90(m, 1H), 7.07(m, 1H), 7.14(m, 1H), 7.63 (dd, 1H),8.21(d, 1H); APCI m/z 396 [M + H]⁺ 31 2-CH₃, OCH₃ APCI m/z 412 [M + H]⁺76% 3-OCH₃ NMR spectra were run at 400 MHz in CDCl₃; *except example 15(LCMS)

Example 3

4-hydroxy-3-methyl-benzonitrile can be prepared as described in J. Med.Chem.; 1999, 42, 3572

Example 31

3-methoxy-2-methyl-phenol can be prepared as described in J. Org. Chem.,1990, 55(5), 1466-71

Example 25A Crystallisation of Example 25

The compound of Example 25 was dissolved in hot ethyl acetate andallowed to cool, with gentle stirring, to room temperature. Thecrystalline material was isolated by filtration.

Single Crystal X-Ray Diffraction Experimental

The crystal structure was determined by Single Crystal X-Ray diffractionat room temperature and ambient relative humidity using a Bruker SMARTAPEX Single Crystal X-Ray diffractometer and Mo Kα radiation.Intensities were integrated (SMART v5.622 (control) and SAINT v6.02(integration) software, Bruker AXS Inc., Madison, Wis. 1994) fromseveral series of exposures where each exposure covered 0.3° in ω, withan exposure time of 30 s and the total data set was more than a sphere.Data were corrected for absorption using the multiscans method (SADABS,Program for scaling and correction of area detector data, G. M.Sheldrick, University of Göttingen, 1997 (based on the method of R. H.Blessing, Acta Cryst. 1995, A51, 33-38)).

The crystal structure was successfully solved by direct methods usingSHELXS-97 (SHELXS-97, Program for crystal structure solution. G. M.Sheldrick, University of Göttingen, Germany, 1997, release 97-2), inSpace Group P1 and refined by the method of least-squares usingSHELXL-97 (SHELXL-97, Program for crystal structure refinement. G. M.Sheldrick, University of Göttingen, Germany, 1997, release 97-2), to afinal refined R-Factor of 5.16% (I>3σl).

Powder X-Ray Diffraction

The X-ray diffraction data were collected at room temperature using aBruker AXS D4 powder X-ray diffractometer (Cu Kα radiation) fitted withan automatic sample changer, a theta-theta goniometer, automatic beamdivergence slits, a secondary monochromator and a scintillation counter.The powder was mounted on a 12 mm diameter a silicon wafer specimenholder. The sample was rotated while being irradiated with Copper Kα1X-rays (wavelength=1.5406 Angstroms) with the X-ray tube operated at 40kV/40 mA. The analyses were performed with the goniometer running incontinuous mode set for a 5 second count per 0.02° step over a two thetarange of 2° to 55°. The PXRD pattern of Example 25A exhibited thefollowing characteristic diffraction peaks

2θ ± 0.1 (/°) 23.7 24.6 10.7 16.2 14.1 18.3 8.5Calculation of the Powder X-Ray Diffraction Pattern from the CrystalStructure

2θ angles, d-spacings and relative intensities (Table I) were calculatedfrom the single crystal structure of Example 25A using the “ReflexPowder Diffraction” module of Accelrys MS Modelling™ [version 3.0].Pertinent simulation parameters were:

Wavelength=1.5406 Å (Cu Kα)

Polarisation Factor=0.5

Pseudo-Voigt Profile (U=0.01, V=−0.001, W=0.002)

The calculated pattern represents that of a pure phase of Example 25Asince it is derived from a single crystal structure. A comparison of themeasured and calculated patterns is shown in Figure I and demonstratesthat the bulk is represented by the single crystal structure. Slightdiscrepancies between peak intensities can be attributed to preferredorientation effects in the measured pattern.

Relative d-spacing Intensity 2θ (/°) (/Å) (%) 23.665 3.75659 100.024.630 3.61162 57.3 10.651 8.29949 54.1 16.233 5.45598 46.6 22.6793.91773 46.1 14.081 6.28441 45.0 18.267 4.85284 45.0 26.797 3.32421 44.323.363 3.80449 43.5 21.032 4.22049 43.1 20.211 4.39022 38.8 8.53710.34867 36.4 21.989 4.03895 36.4 24.423 3.64172 36.4 16.590 5.3393935.1 27.952 3.18941 35.0 47.788 1.90176 35.0 32.790 2.72905 34.6 12.3807.14378 34.2 15.518 5.70563 34.1 17.916 4.94700 34.1 31.339 2.85203 32.721.399 4.14897 32.0 26.443 3.36793 30.5 28.123 3.17044 29.9 17.5435.05134 29.5 24.128 3.68558 29.0 27.188 3.27729 28.9 36.726 2.44512 28.243.671 2.07100 28.1 19.807 4.47873 27.7 13.309 6.64728 27.5 26.1253.40815 27.4 35.806 2.50582 27.1 33.788 2.65067 26.9 42.356 2.13222 26.741.711 2.16367 26.4 17.151 5.16594 26.3 43.147 2.09496 26.3 34.2912.61300 26.2 15.162 5.83898 26.1 31.085 2.87480 26.1 32.306 2.76883 26.150.445 1.80765 26.0 25.827 3.44685 25.9 49.156 1.85200 25.6 11.7677.51482 25.5 38.739 2.32257 25.5 7.731 11.42585 24.5

Example 321-[5-Isopropyl-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]azetidin-3-ylmethanesulfonate

The title compound was prepared from the product of preparation 7 and3-fluorophenol, using a similar method to that of example 1. After 16hours (c.f. 40 hours in example 1), tlc analysis indicated that thereaction was complete, affording the desired product in 38% yield. ¹HNMR (400 MHz, CDCl₃) δ: 1.23 (d, 6H), 2.67 (m, 1H), 3.92 (m, 2H), 4.00(s, 3H), 4.12 (m, 2H), 4.85 (m, 1H), 6.38 (d, 1H), 6.44 (dd, 1H), 6.66(m, 1H), 6.91 (d, 1H), 7.18 (m, 1H), 7.49 (dd, 1H), 8.11 (d, 1H); LRMSESI m/z 384 [M+H]⁺.

Example 333-{3-[3-(5-Fluorophenoxy)azetidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-6-methoxy-2-methylpyridine

Sodium hydride (60% dispersion in mineral oil, 22.4 mg, 0.56 mmol) wasadded to a solution of 5-fluorophenol (62.8 mg, 0.56 mmol) inN,N-dimethylformamide (2 mL) and the mixture was stirred at roomtemperature until effervescence had ceased. The product of preparation16 (100 mg, 0.28 mmol) was then added and the mixture was heated at 100°C. for 18 hours. Further sodium hydride (60% dispersion in mineral oil,11.2 mg, 0.28 mmol) and 5-fluorophenol (31.4 mg, 0.28 mmol) was thenadded and heating continued for a further 24 hours. The cooled reactionmixture was then diluted with water (20 mL) and brine (40 mL) and wasextracted with ethyl acetate (2×30 mL). The combined organic solutionwas then magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 95:5, to afford the title compound in27% yield, 30 mg. ¹H NMR (CDCl₃, 400 MHz) δ: 2.15 (s, 3H), 2.24 (s, 3H),3.92 (m, 2H), 3.98 (s, 3H), 4.14 (m, 1H), 4.19 (m, 1H), 4.90 (m, 1H),6.40 (m, 1H), 6.44 (d, 1H), 6.70 (m, 2H), 7.20 (m, 1H), 7.41 (d, 1H);LRMS ESI⁺ m/z 369 [M+H]⁺.

Example 343-{3-[3-(4-Fluoro-2-methylphenoxy)azetidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-6-methoxy-2-methylpyridine

The title compound was prepared from the product of preparation 16 and4-fluoro-3-methylphenol, using the same method as that described forexample 33, in 34% yield.

¹H NMR (CDCl₃, 400 MHz) δ: 2.13 (s, 3H), 2.18 (s, 3H), 2.24 (s, 3H),3.91 (m, 1H), 3.96 (m, 1H), 3.99 (s, 3H), 4.04 (m, 1H), 4.14 (m, 1H),4.85 (m, 1H), 6.32 (m, 1H), 6.75 (m, 2H), 6.84 (m, 1H), 7.39 (d, 1H);LRMS ESI⁺ m/z 383 [M+H]⁺

Example 355-{3-[3-(3-Fluorophenoxy)-3-methylazetidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine

A solution of the product of preparation 12 (75 mg, 0.2 mmol),acetylhydrazide (44.4 mg, 0.6 mmol) in ethanol (3 mL) was heated over 4Å molecular sieves, at 50° C. for 18 hours. The reaction mixture wasthen concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol,100:0 to 95:5, to afford the title compound in 26% yield. ¹H NMR (CDCl₃,400 MHz) δ: 1.65 (s, 3H), 2.21 (s, 3H), 3.82 (d, 2H), 4.04 (s, 3H), 4.18(d, 2H), 6.40 (m, 2H), 6.66 (t, 1H), 6.92 (d, 1H), 7.19 (m, 1H), 7.59(m, 1H), 8.16 (d, 1H); LRMS ESI⁺ m/z 369 [M+H]⁺.

Example 365-[3-[3-(3-Fluorophenoxy)-3-methylazetidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine

The title compound was prepared from the products of preparations 12 and5, using the same method as that described for example 35, in 27% yield.¹H NMR (CDCl₃, 400 MHz) δ: 1.63 (s, 3H), 3.30 (s, 3H), 3.84 (d, 2H),3.99 (s, 3H), 4.18 (d, 2H), 4.30 (s, 2H), 6.38 (m, 2H), 6.65 (t, 1H),6.86 (d, 1H), 7.17 (m, 1H), 7.62 (m, 1H), 8.21 (d, 1H); LRMS ESI⁺ m/z400 [M+H]⁺.

Example 375-{3-[4-(3,4-Difluorophenoxy)piperidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine

The product of preparation 21 (67.4 mg, 0.23 mmol) and3,4-difluorophenol (50.85 mg, 0.47 mmol) were added to mixture ofpolymer supported triphenylphosphine (403 mg, 0.61 mmol) anddi-tert-butyl azodicarboxylate (107 mg, 0.47 mmol) in dichloromethane (2mL) and the mixture was stirred at room temperature for 4 hours.Trifluoroacetic acid (0.78 mL) was then added and the mixture wasstirred for a further hour. The reaction mixture was basified with 2Msodium hydroxide solution (5 mL) and the organic layer was separated andconcentrated in vacuo. Purification of the residue by HPLC using aPhenomenex Luna C18 system, eluting withwater/acetonitrile/trifluoroacetic acid (5:95:0.1):acetonitrile, 95:5 to5:95, afforded the title compound as a gum in 32% yield, 29.8 mg. ¹H NMR(CDCl₃, 400 MHz) δ: 1.69-1.80 (m, 2H), 1.89-1.95 (m, 2H), 2.31 (s, 3H),3.02-3.12 (m, 2H), 3.31-3.40 (m, 2H), 4.01 (s, 3H), 4.30-4.80 (m, 1H),6.52-6.60 (m, 1H), 6.64-6.70 (m, 1H), 6.80 (d, 1H), 6.98-7.02 (m, 1H),7.56 (dd, 1H), 8.08 (s, 1H); LRMS ESI m/z 402 [M+H]⁺.

Examples 38 to 53

The following compounds, of the general formula shown below, wereprepared from the products of preparation 21 (examples 38-45) andpreparation 42 (examples 39-53) and the appropriate commercial phenol orphenol known in the literature as outlined below, using the same methodto that described example 37.

No. X′_(n) R² Data (LRMS* and/or ¹H NMR) Yield 38 2-CH₃, 6-CH₃ H δ:1.69-1.80(m, 2H), 1.88-1.97(m, 2H), 10% 2.03(s, 6H), 2.09(s, 3H),2.85-2.96(m, 2H), 3.38-3.45(m, 2H), 3.82-3.91(m, 1H), 4.01(s, 3H),6.87-7.01(m, 4H), 7.59(d, 1H), 8.18(s, 1H); APCI m/z 394 [M + H]⁺ 392-CH₃, 3-OCH₃ H δ: 1.71-1.81(m, 2H), 1.86-1.97(m, 2H), 36% 2.07(s, 3H),2.25(s, 3H), 3.00-3.10(m, 2H), 3.00-3.39(m, 2H), 3.80(s, 3H), 4.00(s,3H), 4.36-4.42(m, 1H), 6.46- 6.51(m, 2H), 6.90(d, 1H), 7.01-7.10(m, 1H),7.59(dd, 1H), 8.16(m, 1H); APCI m/z 410 [M + H]⁺ 40 H H δ: 1.68-1.76(m,2H), 1.89-1.96(m, 2H), 22% 2.25(s, 3H), 2.97-3.03(m, 2H), 3.30- 3.36(m,2H), 3.99(s, 3H), 4.37-4.42(m, 1H), 6.85-6.94(m, 4H), 7.22-7.27(m, 2H),7.54(dd, 1H), 8.12(m, 1H); APCI m/z 366 [M + H]⁺ 41 2-F, 3-F H APCI m/z402 [M + H]⁺ 19% 42 3-F, 5-F H HRMS m/z found 402.1736; 7% C₂₀H₂₁F₂N₅O₂requires 402.1726 [M + H]⁺ 43 2-CH₃, 4-F H HRMS m/z found 398.1967; 18%C₂₁H₂₄FN₅O₂ requires 398.1987 [M + H]⁺ 44 2 CH₃, 5-CN H HRMS m/z found405.2034; 15% C₂₂H₂₄N₆O₂ requires 405.2017 [M + H]⁺ 45 2 CH₃, 3-F H HRMSm/z found 398.1974; 14% C₂₁H₂₄FN₅O₂ requires 398.1987 [M + H]⁺ 46 2-CH₃,5-CN OCH₃ ESI m/z 435 [M + H]⁺ 5% 47 2-CH₃, 5-F OCH₃ ESI m/z 428 [M +H]⁺ 7% 48 2-CH₃, 3-F OCH₃ ESI m/z 428 [M + H]⁺ 5% 49 2-CH₃, 4-F OCH₃ ESIm/z 428 [M + H]⁺ 13% 50 2-CH₃, 5-OCH₃ OCH₃ ESI m/z 439 [M + H]⁺ 7% 512-CH₃, 4-CN OCH₃ ESI m/z 435 [M + H]⁺ 7% 52 3-F, 5-F OCH₃ ESI m/z432[M + H]⁺ 12% 53 3-F, 4-F OCH₃ δ: 1.71-1.81(m, 2H), 1.90-1.99(m, 2H),21% 3.14-3.22(m, 2H), 3.31(s, 3H), 3.39- 3.48(m, 2H), 4.00(s, 3H),4.30-4.39(m, 3H), 6.58(m, 1H), 6.63-6.69(m, 1H), 6.80(d, 1H),7.00-7.09(m, 1H), 7.77(dd, 1H), 8.29(m, 1H); ESI m/z 432 [M + H]⁺ NMRspectra were run at 400 MHz in CDCl3; *except examples 42-45 (HRMS)

Example 40

diisopropyl azodicarboxylate used instead of di-tert-butylazodicarboxylate

Examples 43

crude products were purified by HPLC using a Phenomenex Luna C18 system,eluting with 0.1% formic acid (aqueous):0.1% formic acid/acetonitrile,100:0 to 2:98.

Example 44

3-hydroxy-4-methyl-benzonitrile can be prepared as described in WO96/24609, p 20

Example 45

3-fluoro-2-methyl-phenol can be prepared as described EP 511036, p 32

Examples 46-52

crude compounds were purified by HPLC using a Phenomenex Luna C18system, eluting with 0.1% formic acid (aqueous):0.1% formicacid/acetonitrile, 100:0 to 2:98.

Example 542-Methoxy-5-{3-[4-(2-methoxyphenoxy)piperidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}pyridine

Diisopropylazodicarboxylate (176 μL, 0.69 mmol) in tetrahydrofuran (2mL) was added to an ice-cooled mixture of the product of preparation 21(200 mg, 0.69 mmol), 2-methoxyphenol (86 mg, 0.69 mmol) and polymersupported triphenylphosphine (238 mg, 0.83 mmol) in tetrahydrofuran (2mL)/dichloromethane (0.6 mL) and the mixture was stirred at roomtemperature for 72 hours. The reaction mixture was then diluted withdichloromethane, basified with 2M sodium hydroxide solution and passedthrough a phase separation tube. The organic solution was concentratedin vacuo and the residue was purified by column chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 99:1:0.1 to95:5:0.5. The appropriate fractions were evaporated under reducedpressure and the residue was further purified by HPLC using a PhenomenexLuna C18 system, eluting with water/acetonitrile/trifluoroacetic acid(5:95:0.1):acetonitrile, 95:5 to 5:95. The appropriate fractions wereevaporated under reduced pressure and the residue was washed with sodiumhydrogen carbonate solution and extracted with dichloromethane. Theorganic solution was then dried over sodium sulfate and concentrated invacuo to give an oil. Trituration of the oil afforded the title compoundas a solid in 21% yield, 58 mg. ¹H NMR (CDCl₃, 400 MHz) δ: 1.70-1.79 (m,2H), 1.90-1.97 (m, 2H), 2.25 (s, 3H), 2.94-3.00 (m, 2H), 3.34-3.40 (m,2H), 3.82 (s, 3H), 4.00 (s, 3H), 4.29-4.35 (m, 1H), 6.82-6.96 (m, 5H),7.55 (dd, 1H), 8.12 (m, 1H); LRMS APCI m/z 396 [M+H]⁺.

Example 553-({1-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)-2-methylpyridine

Potassium tert-butoxide (31 mg, 0.28 mmol) was added to a solution ofthe product of preparation 24 (90.1 mg, 0.25 mmol) in tetrahydrofuran (3mL) and the reaction was stirred at room temperature for 30 minutes.Methyl p-toluenesulfonate (51.4 mg, 0.28 mmol) was then added and themixture was stirred for 3 hours. The reaction mixture was thenconcentrated in vacuo and re-dissolved in dichloromethane. The organicsolution was washed with sodium hydrogen carbonate solution, dried overmagnesium sulfate and concentrated in vacuo. The residue wasre-dissolved in tetrahydrofuran (3 mL) and trifluoroacetic acid (onedrop) and acethydrazide (42 mg, 0.56 mmol) was added and the mixture washeated under reflux for 4 hours. The reaction mixture was thenconcentrated in vacuo and re-dissolved in dichloromethane. The organicsolution was washed with sodium hydrogen carbonate solution and brine,dried over magnesium sulfate and concentrated in vacuo to give an oil.The oil was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 90:10, to afford the title compound as ared oil in 52% yield, 46.5 mg. ¹H NMR (DMSO-d₆, 400 MHz) δ: 1.69-1.81(m, 2H), 1.90-2.02 (m, 2H), 2.25 (s, 3H), 2.50 (s, 3H), 3.00-3.10 (m,2H), 3.30-3.39 (m, 2H), 4.00 (s, 3H), 4.40 (m, 1H), 6.90 (d, 1H), 7.12(m, 2H), 7.55 (d, 1H), 8.10 (m, 1H), 8.15 (m, 1H); LRMS APCI m/z 381[M+H]⁺.

Examples 56 to 63

The following compounds, of the general formula shown below, wereprepared using the same method to that described for example 55. Theproducts of preparations 37, 47 and 51 were treated with acethydrazideto afford examples 56 to 58. Likewise, the products of preparations 35,37, 47, 48 and 51 were treated with 2-methoxyacetylhydrazide(preparation 5) to afford examples 59 to 63.

No. R¹ R² X Data (LRMS* and/or ¹H NMR Yield 56

H O δ: 1.72-1.82(m, 2H), 1.92-2.00(m, 2H), 2.15(s, 3H), 2.26(s, 3H),3.02-3.09(m, 2H), 3.29-3.37(m, 2H), 3.98(s, 3H), 4.52-4.59(m, 1H),6.65(d, 1H), 6.91(d, 1H), 7.75(d, 1H), 8.16(m, 1H), 8.22- 8.31(m, 2H);APCI m/z 381 [M + H]⁺  7% 57

H O δ: 1.75-1.85(m, 2H), 1.90-2.05(m, 2H), 2.25(s, 3H), 3.05-3.15(m,2H), 3.35- 3.45(m, 2H), 4.00(s, 3H), 4.40-4.50(m, 1H), 6.85-6.95(m, 3H),7.15-7.20(m, 1H), 7.30-7.35(d, 1H), 7.57-7.62(m, 1H), 8.15(s, 1H); APCIm/z 400 [M + H]⁺ 55% 58

H NCH₃ APCI m/z 380 [M + H]⁺ 52% 59

OCH₃ O δ: 1.75-1.82(m, 2H), 1.89-1.99(m, 2H), 2.20(s, 3H), 3.02-3.09(m,2H), 3.30-3.41(m, 5H), 3.99(s, 3H), 4.32(s, 3H), 4.40-4.45(m, 1H),6.78-6.85(m, 3H), 7.08-7.15(m, 2H), 7.65(dd, 1H), 8.25(m, 1H); APCI m/z410 [M + H]⁺ 48% 60

OCH₃ O δ: 1.77-1.86(m, 2H), 1.93-2.01(m, 2H), 2.15(s, 3H), 2.06(s, 3H),3.06- 3.15(m, 2H), 3.22-3.40(m, 5H), 3.99(s, 3H), 4.36(s, 2H), 6.63(d,1H), 6.89(d, 1H), 7.64(d, 1H), 8.23-8.31(m, 3H); APCI m/z 411 [M + H]⁺54% 61

OCH₃ O δ: 1.80-1.90(m, 2H), 1.95-2.05(m, 2H), 3.12-3.22(m, 2H), 3.32(s,3H), 3.40-3.50(m, 2H), 4.00(s, 3H), 4.35(s, 2H), 4.45-4.55(m, 1H),6.85-6.95(m, 3H), 7.15-7.20(m, 1H), 7.35-7.38(m, 1H), 7.70-7.75(m, 1H),8.27(s, 1H); APCI m/z 430 [M + H]⁺ 30% 62

OCH₃ O δ: 1.75-1.85(m, 2H), 1.92-2.04(m, 2H), 3.18-3.09(m, 2H), 3.32(s,3H), 3.40-3.49(m, 2H), 4.00(s, 3H), 4.35(s, 2H), 4.39-4.44(m, 1H),6.35-6.44(m, 3H), 6.92(d, 1H), 6.88(m, 1H), 7.78(m, 1H), 8.29(m, 1H);ESI m/z 432 [M + H]⁺ 58% 63

OCH₃ NCH₃ APCI m/z 410 [M + H]⁺ 25% NMR spectra were run at 400 MHz inCDCl₃ or DMSO-d₆ (examples 56 and 60)

Example 58

further trifluoroacetic acid (few drops) and 2.0 eq acethydrazide afterheating under reflux for 2 hours.

Example 63

further trifluoroacetic acid (few drops) and 2.0 eq2-methoxyacetylhydrazide (preparation 5) after heating under reflux for2 hours.

Examples 64 to 72

The following compounds, of the general formula shown below, wereprepared using the same method to that described preparation 4. Theproducts of preparations 38, 39, 41 58 and 61 were treated withacethydrazide to afford examples 64 to 68. Likewise, the products ofpreparation 38, 41 58 and 61 were treated with 2-methoxyacetylhydrazide(preparation 5) to afford examples 69 to 72.

No. R² R¹ Data (LRMS and/or ¹H NMR) Yield 64

H ESI m/z 381 [M + H]⁺ 53% 65

H APCI m/z 380 [M + H]⁺ 66

H APCI m/z 395 [M + H]⁺ 20% 67

H ESI m/z 367 [M + H]⁺ 30% 68

H APSI m/z 391 [M + H]⁺ 37% 69

OCH₃ δ: 1.71-1.83(m, 2H), 1.92-2.00 (m, 2H), 2.17(s, 3H), 3.08- 3.15(m,2H), 3.31-3.40(m, 5H), 3.99(s, 3H), 4.36(s, 2H), 5.20-5.25(m, 1H),6.75(m, 56% 1H), 6.85(m, 1H), 7.38(m, 1H), 7.65(dd, 1H), 7.92(m, 1H),8.27(m, 1H); ESI m/z 411 [M + H]⁺ 70

OCH₃ APCI m/z 425 [M + H]⁺ 33% 71

OCH₃ δ: 1.71-1.81(m, 2H), 1.90-2.00 (m, 2H), 2.99-3.10(m, 2H), 3.29(s,3H), 3.31-3.39(m, 2H), 3.99(s, 3H), 4.32(s, 2H), 4.52- 4.59(m, 1H),6.79-6.87(m, 31% 3H), 6.63(m, 1H), 7.38(m, 1H), 7.65(dd, 1H), 7.92(m,1H), 8.22(m, 1H), 8.38-8.45 (m, 1H); ESI m/z 397 [M + H]⁺ 72

OCH₃ APSI m/z 421 [M + H]⁺ 67% NMR spectra were run at 400 MHz in CDCl₃

Example 73N-{1-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-yl}-N-methylpyrimidin-2-amine

A mixture of the product of preparation 57 (101 mg, 0.33 mmol),2-chloropyrimidine (46 mg, 0.40 mmol) and N,N-diisopropylethylamine (87μL, 0.5 mmol) in dimethylsulfoxide (2 mL) was heated at 100° C. for 2hours. Further 2-chloropyrimidine (46 mg, 0.4 mmol) andN,N-diisopropylethylamine (87 μL, 0.5 mmol) were added and heatingcontinued at 100° C. for 4 hours and at 120° C. for 12 hours. Thereaction mixture was then partitioned between dichloromethane and waterand the organic layer was separated and washed with 10% citric acid (2×5mL). The aqueous solution was basified with sodium hydrogen carbonatesolution and extracted with dichloromethane (3×10 mL). The combinedorganic solution was dried over magnesium sulfate, concentrated in vacuoand the residue was purified by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 99:1:0.1 to95:5:0.5, to afford the title compound as a foam in 56% yield, 70 mg.LRMS APCI 381 [M+H]⁺.

Examples 74 to 108

The following compounds, of the general formula shown below, wereprepared using the same method to that described for example 1, usingeither the product of preparation 4 (examples 74-91) or the product ofpreparation 6 (examples 92-108) with 3 to 5 equivalents of commerciallyavailable phenols or compounds known in the literature, as outlinedbelow.

No. R¹ R² Data (LRMS and/or ¹H NMR) Yield 74

H ESI m/z 410 [M + H]⁺  8% 75

H ESI m/z 386 [M + H]⁺ 33% 76

H δ: 2.04(s, 3H), 2.13(s, 3H), 2.20(s, 3H), 3.97(m, 2H), 4.00(s, 3H),4.14(m, 2H), 4.86(m, 1H), 6.25(d, 1H), 6.78(d, 1H), 6.89(d, 1H), 6.95(m,1H), 7.53(dd, 1H), 8.12(d, 1H); ESI m/z 366 [M + H]⁺ 23% 77

H δ: 2.16(s, 6H), 2.23(s, 3H), 4.04(m, 5H), 4.13(m, 2H), 4.58(m, 1H),6.91(m, 2H), 6.97(m, 2H), 7.58(dd, 1H), 8.15(d, 1H); ESI m/z 366 [M +H]⁺ 19% 78

H ESI m/z 366 [M + H]⁺ 26% 79

H δ: 1.16(t, 3H), 2.20(s, 3H), 2.57(m, 2H), 3.94(m, 2H), 4.03(s, 3H),4.12(m, 2H), 4.86(m, 1H), 6.34(m, 1H), 6.73(m, 1H), 6.86(m, 2H),7.50(dd, 1H), 8.13(d, 1H); ESI m/z 384 [M + H]⁺ 26% 80

H δ: 2.18(s, 3H), 4.00(m, 5H), 4.15(m, 2H), 4.88(m, 1H), 6.23(dd, 1H),6.63(m, 1H), 6.89(d, 1H), 7.27(m, 1H), 7.52(dd, 1H), 8.13(m, 1H); APCIm/z 390 [M + H]⁺ 67% 81

H δ: 2.19(s, 3H), 4.00(m, 5H), 4.08(m, 2H), 4.85(m, 1H), 6.88(d, 1H),6.96(m, 2H), 7.13(m, 1H), 7.51(dd, 1H), 8.11(d, 1H); APCI m/z 390 [M +H]⁺ 35% 82

H δ: 2.21(s, 3H), 4.02(m, 5H), 4.18(m, 2H), 4.91(m, 1H), 6.08(m, 1H),6.58(m, 1H), 6.92(d, 1H), 7.13(m, 1H), 7.52(dd, 1H), 8.14(d, 1H); APCIm/z 408 [M + H]⁺ 39% 83

H APCI m/z 391 [M + H]⁺ 64% 84

H APCI m/z 382 [M + H]⁺ 60% 85

H δ: 2.12(s, 3H), 4.01(m, 5H), 4.20(m, 2H), 4.78(m, 1H), 6.90(d, 1H),6.96(m, 1H), 7.25(d, 2H), 7.53(dd, 1H), 8.12(d, 1H); APCI m/z 406 [M +H]⁺ 34% 86

H δ: 2.21(s, 3H), 3.92(m, 2H), 4.02(s, 3H), 4.15(m, 2H), 4.82(m, 1H),6.55(m, 1H), 6.70(m, 1H), 6.90(d, 1H), 7.02(m, 1H), 7.50(dd, 1H),8.13(d, 1H); APCI m/z 390 [M + H]⁺ 92% 87

H APCI m/z 370 [M + H]⁺ 43% 88

H APCI m/z 374 [M + H]⁺ 65% 89

H APCI m/z 390 [M + H]⁺ 43% 90

H APCI m/z 370 [M + H]⁺ 72% 91

H APCI m/z 373 [M + H]⁺ 67% 92

OCH₃ δ: 2.16(s, 3H), 3.29(s, 3H), 3.99(s, 3H), 3.92-4.02(m, 2H), 4.17(m,2H), 4.31(s, 2H), 4.87(m, 1H), 6.28(m, 1H), 6.73(m, 1H), 6.82-6.90(m,2H), 7.62(m, 1H), 8.21(m, 1H); APCI m/z 400 [M + H]⁺ 67% 93

OCH₃ δ: 2.12(s, 3H), 3.29(s, 3H), 3.99(s, 3H), 3.94-4.01(m, 2H), 4.18(m,2H), 4.31(s, 2H), 4.88(m, 1H), 6.09(m, 1H), 6.56(m, 1H), 6.87(m, 1H),7.04(m, 1H), 7.60(m, 1H), 8.20(d, 1H); APCI m/z 400 [M + H]⁺ 71% 94

OCH₃ δ: 3.29(s, 3H), 4.00(s, 3H), 4.06(dd, 2H), 4.28(m, 2H), 4.31(s,2H), 4.95(m, 1H), 6.29(dd, 1H), 6.65(m, 1H), 6.87(m, 1H), 7.30(dd, 1H),7.65(dd, 1H), 8.22(m, 1H); APCI m/z 420/422 [M + H]⁺ 71% 95

OCH₃ δ: 3.29(s, 3H), 4.00(s, 3H), 4.13(m, 4H), 4.31(s, 2H), 4.91(m, 1H),6.86(d, 1H), 6.94-7.00(m, 2H), 7.13(s, 1H), 7.63(dd, 1H), 8.21(m, 1H);APCI m/z 420/422 [M + H]⁺ 54% 96

OCH₃ δ: 3.29(s, 3H), 4.00(s, 3H), 4.05(m, 2H), 4.28(m, 2H), 4.31(s, 2H),4.95(m, 1H), 6.11(m, 1H), 6.58(m, 1H), 6.87(d, 1H), 7.64(dd, 1H),8.22(m, 1H); APCI m/z 438/440 [M + H]⁺ 47% 97

OCH₃ δ: 3.29(s, 3H), 4.00(s, 3H), 4.15(m, 2H), 4.26(m, 2H) 4.31(s, 2H),4.83(m, 1H), 6.87(d, 1H), 6.98(dd, 2H), 7.23-7.29(m, 2H), 7.64(dd, 1H),8.22(m, 1H); APCI m/z 436/438/440 [M + H]⁺ 61% 98

OCH₃ APCI m/z 421 [M + H]⁺ 53% 99

OCH₃ APCI m/z 400 [M + H]⁺ 73% 100 

OCH₃ APCI m/z 420/422 [M + H]⁺ 82% 101 

OCH₃ APCI m/z 420/422 [M + H]⁺ 70% 102 

OCH₃ APCI m/z 400 [M + H]⁺ 84% 103 

OCH₃ APCI m/z 404 [M + H]⁺ 73% 104 

OCH₃ ESI m/z 440 [M + H]⁺  6% 105 

OCH₃ ESI m/z 440 [M + H]⁺ 28% 106 

OCH₃ ESI m/z 386 [M + H]⁺ 28% 107 

OCH₃ APCI m/z 383 [M + H]⁺ 75% 108 

OCH₃ APCI m/z 418 [M + H]⁺ 99% NMR spectra were run at 400 MHz in CDCl₃

Example 84

3-methoxy-2-methyl-phenol can be prepared as described in J. Med. Chem.1990, 33, 614

Examples 95-98

Crude compounds were triturated with diethyl ether

Example 106

1,5-dimethyl-1H-pyrazol-3-ol can be prepared as described inTetrahedron, 1998, 54, 9393

Example 1094-({1-[4-(6-Methoxy-2-methylpyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]azetidin-3-yl}oxy)-3-methylbenzonitrile

The title compound was prepared from the products of preparations 16 and70, using the same method as that described for example 1, as a palebrown solid in 51% yield. ¹H NMR (400 MHz, CDCl₃) δ: 2.12 (s, 3H), 2.18(s, 3H), 2.23 (s, 3H), 3.88 (s, 1H), 3.95 (s, 4H), 4.06 (s, 1H), 4.15(s, 1H), 4.93 (s, 1H), 6.41 (d, 1H), 6.69 (d, 1H), 7.37 (d, 1H), 7.40(m, 2H)

Example 1102-Methoxy-5-[3-methyl-5-(3-phenoxyazetidin-1-yl)-4H-1,2,4-triazol-4-yl]pyridine

The title compound was prepared from the product of preparation 65 andacetylhydrazide, using the same method as that described for preparation4, in 89% yield.

LRMS ESI m/z 358 [M+H]⁺.

Example 111[5-[3-(2-Chloro-4-fluorophenoxy)azetidin-1-yl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]methanol

A mixture of the products of preparations 81 (300 mg, 0.8 mmol) and 80(360 mg, 4 mmol) in butanol (5 mL) was heated under reflux for 18 hours.The reaction mixture was then cooled to room temperature concentrated invacuo and the residue was purified by HPLC using a Phenomenex Luna C18system, eluting with water/acetonitrile/trifluoroacetic acid(5:95:0.1):acetonitrile, 95:5 to 5:95, to afford the title compound as aclear oil in 6% yield.

LRMS ESI m/z 406 [M+H]⁺

Example 1125-[3-[3-(2-Chloro-4-fluorophenoxy)azetidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine

Potassium tert-butoxide (4 g, 35.42 mmol) was added portionwise to anice-cooled solution of the product of preparation 80 (10.86 g, 29.52mmol) in tetrahydrofuran (100 mL) and the reaction was stirred at roomtemperature for 20 minutes. Methyl p-toluenesulfonate (51.4 mg, 0.28mmol) was then added and the mixture was stirred for 40 minutes. Thereaction mixture was then concentrated in vacuo and partitioned betweenethyl acetate (150 mL) and water (50 mL). The organic layer wasseparated washed with water and brine, dried over magnesium sulfate andconcentrated in vacuo. The residue was re-dissolved in tetrahydrofuran(75 mL) and trifluoroacetic acid (1.2 mL), 2-methoxyacetylhydrazide(preparation 5, 6.15 g, 59.04 mmol) was added and the mixture was heatedunder reflux for 90 minutes. The reaction mixture was then concentratedin vacuo and re-dissolved in ethyl acetate. The organic solution waswashed with sodium hydrogen carbonate solution and brine, dried overmagnesium sulfate and concentrated in vacuo to give an oil. The oil wasthen triturated with diethyl ether to afford the title compound as asolid in 52% yield, 6.5 g. ¹H NMR (400 MHz, CDCl₃) δ: 3.29 (s, 3H), 3.99(s, 3H), 4.05 (dd, 2H), 4.18 (m, 2H), 4.31 (s, 2H), 4.92 (m, 1H), 6.50(m, 1H), 6.85 (m, 2H), 7.15 (dd, 1H), 7.61 (dd, 1H), 8.22 (d, 1H); LRMSAPCI m/z 420/422 [M+H]⁺.

Examples 113 to 124

A mixture of the appropriate phenol [commercial, unless stated below, (1eq)], caesium carbonate (4 eq) and either the product of preparation 4(1 eq) or preparation 6 (1 eq) in acetonitrile (2 mL) was heated underan atmosphere of nitrogen, at reflux for 24 hours. The crude mixturethen was partitioned between dichloromethane and water and passedthrough a phase separation tube. The organic solution was concentratedin vacuo and the residue was purified by HPLC using a Phenomenex LunaC18 column, eluting with water/0.1% formic acid:acetonitrile/0.1% formicacid, 95:5 to 5:95, to afford the title compound.

No. R¹ R² Data (LRMS and/or ¹H NMR) Yield 113

OCH₃ δ: 2.10(s, 3H), 3.29(s, 3H), 4.00(m, 5H), 4.20(m, 2H), 4.34(s, 2H),4.93(m, 1H), 6.18(d, 1H), 6.67(m, 1H), 6.88(d, 1H), 7.02(m, 1H),7.61(dd, 1H), 8.23(d, 1H); APCI m/z 400 [M + H]⁺ 48% 114

OCH₃ δ: 3.30(s, 3H), 4.00(m, 5H), 4.23(m, 2H), 4.35(s, 2H), 4.90(m, 1H),5.95(d, 1H), 6.43(m, 1H), 6.88(d, 1H), 7.62(dd, 1H), 8.23(d, 1H); APCIm/z 418 [M + H]⁺ 53% 115

OCH₃ APCI m/z 404 [M + H]⁺ 70% 116

OCH₃ δ: 3.32(s, 3H), 4.03(m, 5H), 4.26(m, 2H), 4.36(s, 2H), 5.00(m, 1H),6.78(d, 1H), 6.89(d, 1H), 7.30(m, 2H), 7.62(dd, 1H), 8.12(d, 1H); APCIm/z 427 [M + H]⁺ 41% 117

OCH₃ APCI m/z 427 [M + H]⁺ 41% 118

OCH₃ δ: 3.28(s, 3H), 4.02(m, 5H), 4.30(m, 4H), 5.00(m, 1H), 6.37(d, 1H),6.80(m, 1H), 6.88(d, 1H), 7.37(m, 1H), 7.65(dd, 1H), 8.23(d, 1H); APCIm/z 454 [M + H]⁺ 50% 119

H δ: 2.10(s, 3H), 2.22(s, 3H), 3.98(m, 2H), 4.02(s, 3H), 4.18(m, 2H),4.91(m, 1H), 6.17(d, 1H), 6.66(m, 1H), 6.91(d, 1H), 7.02(m, 1H),7.55(dd, 1H), 8.14(d, 1H); APCI m/z 370 [M + H]⁺ 48% 120

H δ: 2.04(s, 3H), 2.22(s, 3H), 3.97(m, 2H), 4.03(s, 3H), 4.22(m, 2H),4.90(m, 1H), 5.97(d, 1H), 6.43(s, 1H), 6.90(d, 1H), 7.58(dd, 1H),8.16(d, 1H); APCI m/z 388 [M + H]⁺ 39% 121

H APCI m/z 397 [M + H]⁺ 11% 122

H APCI m/z 397 [M + H]⁺ 19% 123

H APCI m/z 424 [M + H]⁺ 22% 124

H APCI m/z 424 [M + H]⁺ 0.1%  NMR spectra were run at 400 MHz in CDCl₃

Example 120

3,5-Difluoro-2-methylphenol was prepared as described in preparation 68

Example 121

2-chloro-3-hydroxybenzonitrile was prepared as described in preparation72

Example 122

3-chloro-4-hydroxybenzonitrile was prepared as described in preparation71

Example 123

3-fluoro-2-(trifluoromethyl)phenol was prepared as described inpreparation 73

Example 1251-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]azetidin-3-ol

A mixture of the product of preparation 82 (135 mg, 0.52 mmol) and3,4,5-trichloropyridine (94 mg, 0.52 mmol) in dimethylsulfoxide (5 mL)was stirred at room temperature for 24 hours. The reaction mixture wasthen partitioned between dichloromethane and water and the organic layerwas separated, washed with brine, dried over magnesium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with dichloromethane:methanol,100:0 to 95:5, afforded the title compound as a crystalline solid in 43%yield, 90 mg.

¹H NMR (400 MHz, CDCl₃) δ: 2.21 (s, 3H), 4.00 (s, 3H), 4.07 (m, 2H),4.14 (m, 2H), 4.96 (m, 1H), 6.88 (d, 1H), 7.50 (dd, 1H), 8.10 (d, 1H);LRMS ESI m/z 409 [M+H]⁺.

Examples 126 to 128

The following compounds, of the general formula shown below, wereprepared using the same method to that described for example 125, usingthe product of preparation 82 with commercially available phenols orcompounds known in the literature, as outlined below.

No. R¹ R² Data (LRMS) Yield 126

H APCI m/z 373 [M + H]⁺ 50% 127

H APCI m/z 407 [M + H]⁺ 12% 128

H APCI m/z 388 [M + H]⁺ 44%

Example 127

crude compound was twice triturated with diethyl ether

Examples 129 to 138

The following compounds, of the general formula shown below, wereprepared from the products of preparation 21 (examples 129-133) andpreparation 42 (examples 134-138) and 1 to 2 equivalents of theappropriate commercial phenol (or phenol known in the literature asoutlined below), using the same method to that described example 37.

No. R¹ R² Data (LRMS and/or ¹H NMR) Yield 129

H δ: 1.75(m, 2H) 1.95(m, 2H), 2.25(s, 3H) 2.40(s, 3H), 3.30(m, 2H),3.50(m, 2H), 4.00(s, 3H), 4.45(m, 1H), 6.90(d, 1H), 6.98(m, 1H), 7.18(d,2H), 7.55(d, 1H), 8.15(s, 1H); APCI m/z 405 [M + H]⁺ 19% 130

H APCI m/z 381 [M + H]⁺ 16% 131

H APCI m/z 423 [M + H]⁺ 16% 132

H δ: 1.60-2.00(m, 4H), 2.10(s, 3H), 2.25(s, 3H), 2.80(s, 3H), 3.00(m,2H), 3.10(s, 3H), 3.2-3.40(m, 2H), 4.00(s, 3H), 4.40(m, 1H), 6.80(m,2H), 6.90(d, 1H), 7.15(m, 1H), 7.58(d, 1H), 8.17(s, 1H); APCI m/z 451[M + H]⁺  8% 133

H APCI m/z 410 [M + H]⁺  4% 134

OCH₃ δ: 1.80-2.00(m, 4H), 2.40(s, 3H), 3.00- 3.40(m, 7H), 4.00(s, 3H),4.30(m, 2H), 4.50(m, 1H), 6.90(d, 1H), 7.00(m, 1H), 7.20(m, 2H), 7.70(d,1H), 8.25(s, 1H); APCI m/z 435 [M + H]⁺ 33% 135

OCH₃ APCI m/z 481 [M + H]⁺ 17% 136

OCH₃ APCI m/z 455 [M + H]⁺ 12% 137

OCH₃ δ: 1.80(m, 2H), 1.90(m, 2H), 3.00(m, 2H), 3.38(s, 3H), 3.40(m, 2H),4.00(s, 3H), 4.30(s, 2H), 4.40(m, 1H), 6.70-6.80(m, 2H), 6.85(d, 1H),6.90(m, 1H), 7.55(dd, 1H), 8.25(d, 1H); APCI m/z 432 [M + H]⁺ 39% 138

OCH₃ δ: 1.80(m, 2H), 1.90(m, 2H), 2.20(s, 3H), 3.10(m, 2H), 3.30-3.40(m,5H), 4.00(s, 3H), 4.25(s, 2H), 4.40(m, 1H), 6.80(d, 1H), 7.05(d, 1H),7.60(dd, 1H), 8.08(d, 1H), 8.25(d, 1H); APCI m/z 411 [M + H]⁺ 52% NMRspectra were run at 400 MHz in CDCl₃

Example 129

3-Hydroxy-2-methylbenzonitrile was prepared as described in preparation74

Example 131

3-Hydroxy-2-methylbenzamide was prepared as described in preparation 75

Example 132 and 135

3-Hydroxy-N,N,2-trimethylbenzamide was prepared as described inpreparation 76

Example 133

2-(Methoxymethyl)phenol was prepared as described in preparation 77.

Example 136

2-(Dimethylamino)-4-methyl-5-pyrimidinol may be prepared as described inEP 138464, p 22.

Example 1395-{3-[(3S)-3-(2-Chlorophenoxy)pyrrolidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine

A mixture of the product of preparation 110 (200 mg, 0.73 mmol),2-chlorophenol (112 mg, 0.87 mmol), di-tert-butyl azodicarboxylate (235mg, 1.02 mmol) and polymer supported triphenylphosphine (610 mg, 1.83mmol) in dichloromethane (10 mL) was stirred at room temperature for 18hours. The reaction mixture was then filtered, concentrated in vacuo andthe residue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 100:0 to 92:8, to afford the titlecompound as a glass in 74% yield, 209 mg. ¹H NMR (400 MHz, CDCl₃) δ:2.10 (m, 5H) 3.20 (m, 1H), 3.40 (m, 1H), 3.50 (m, 2H), 4.00 (s, 3H),4.80 (m, 1H), 6.80 (m, 3H), 7.15 (m, 1H), 7.30 (d, 1H), 7.50 (d, 1H),8.10 (s, 1H); LRMS APCI m/z 386 [M+H]⁺.

Example 1402-Methoxy-5-{3-methyl-5-[(3S)-3-(2-methylphenoxy)pyrrolidin-1-yl]-4H-1,2,4-triazol-4-yl}pyridine

The title compound was prepared from the product of preparation 110 and2-methylphenol, using the same method as that described for example 139.The crude compound was purified by HPLC using a Phenomenex Luna C18system, eluting with water/acetonitrile/trifluoroacetic acid(5:95:0.1):acetonitrile, 95:5 to 5:95, to afford the desired product in31% yield. LRMS APCI m/z 367 [M+H]⁺.

Example 1413-({1-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)phthalonitrile

Potassium tert-butoxide (42 mg, 0.57 mmol) was added to a solution ofthe product of preparation 21 (150 mg, 0.52 mmol) in tetrahydrofuran (5mL) and the mixture was stirred at room temperature for 30 minutes.3-Fluorophthalonitrile (76 mg, 0.52 mmol) was added and the mixture wasstirred at room temperature for 18 hours. The reaction mixture was thenpartitioned between ethyl acetate and water and the organic layer wasseparated, dried over magnesium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with dichloromethane:methanol, 100:0 to 95:5, to afford thetitle compound as a solid in 37% yield, 79 mg. ¹H NMR (400 MHz, CDCl₃)δ: 1.80 (m, 2H) 2.10 (m, 2H), 2.25 (s, 3H), 3.10 (m, 2H), 3.40 (m, 2H),4.00 (s, 3H), 4.60 (m, 1H), 6.95 (d, 1H), 7.20 (m, 1H), 7.35 (d, 1H),7.60 (m, 2H), 8.15 (s, 1H); LRMS APCI m/z 416 [M+H]⁺.

Example 1423-({1-[5-(Methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)phthalonitrile

The title compound was prepared from the product of preparation 42 and3-fluorophthalonitrile, using the same method as that described forexample 141 as an oil in 31% yield. LRMS APCI m/z 446 [M+H]⁺.

Example 1436-({1-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)-1-methylpyridin-2(1H)-one

The title compound was prepared by sequential treatment of the productof preparation 116 with potassium tert-butoxide and acetylhydrazide,using the same method as that described for example 55, as a solid in76% yield. LRMS APCI m/z 397 [M+H]⁺.

Example 1446-({1-[5-(Methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)-1-methylpyridin-2(1H)-one

The title compound was prepared by sequential treatment of the productof preparation 116 with potassium tert-butoxide and2-methoxyacetylhydrazide (preparation 5), using the same method as thatdescribed for example 55, as a solid in 62% yield. LRMS APCI m/z 427[M+H]⁺.

Examples 145 to 157

The following compounds, of the general formula shown below, wereprepared using the same method to that described preparation 4. Theproducts of preparations 103-109 were treated with acetylhydrazide toafford examples 145 to 150 and with 2-methoxyacetylhydrazide(preparation 5) to afford examples 151 to 157.

No. R¹ R² Data (LRMS and/or ¹H NMR) Yield 145

H APCI m/z 407 [M + H]⁺ 24% 146

H δ: 2.10-2.20(m, 5H), 3.25(m, 1H), 3.40(m, 1H), 3.45-3.50(m, 2H),4.00(s, 3H), 4.90(m, 1H), 6.80-6.90(m, 3H), 7.15(m, 1H), 7.35(dd, 1H),7.50(dd, 1H), 8.10(d, 1H); APCI m/z 386 [M + H]⁺ 52% 147

H APCI m/z 383 [M + H]⁺ 22% 148

H δ: 2.10(m, 5H), 2.15(s, 3H), 3.25(m, 1H), 3.40(m, 2H), 3.48(m, 1H),4.00(s, 3H), 4.80(m, 1H), 6.68(d, 1H), 6.80(m, 1H), 7.10(m, 2H),7.48(dd, 1H), 8.10(d, 1H); APCI m/z 366 [M + H]⁺ 58% 149

H APCI m/z 377 [M + H]⁺ 34% 150

H APCI m/z 370 [M + H]⁺ 77% 151

OCH₃ APCI m/z 437 [M + H]⁺ 41% 152

OCH₃ δ: 2.05-2.15(m, 2H), 3.25(s, 3H), 3.38(m, 1H), 3.45(m, 1H), 3.58(d,1H), 3.65(dd, 1H), 4.00(s, 3H), 4.10- 4.30(m, 2H), 4.95(m, 1H), 6.85(m,2H), 6.95(m, 1H), 7.20(m, 1H), 7.35(dd, 1H), 7.65(dd, 1H), 8.25(d, 1H);APCI m/z 416 [M + H]⁺ 52% 153

OCH₃ δ: 2.00-2.20(m, 2H) 2.25(s, 3H), 3.50(m, 4H), 3.80(s, 3H), 4.00(s,3H), 4.30(m, 2H), 4.90(m, 1H), 6.80(m, 4H), 6.95(m, 1H), 7.60(d, 1H),8.20(s, 1H); APCI m/z 412 [M + H]⁺ 31% 154

OCH₃ δ: 2.05-2.10(m, 5H), 3.20-3.25(m, 4H), 3.35-3.45(m, 2H), 3.50(m,1H), 4.00(s, 3H), 4.25(s, 2H), 4.88(m, 1H), 6.71- 6.81(m, 2H), 6.87(m,1H), 6.89(m, 1H), 6.91-6.97(m, 1H), 7.65(dd, 1H), 8.26(d, 1H); APCI m/z396 [M + H]⁺ 61% 155

OCH₃ APCI m/z 407 [M + H]⁺ 31% 156

OCH₃ APCI m/z 407 [M + H]⁺ 59% 157

OCH₃ APCI m/z 400 [M + H]⁺ 62% NMR spectra were run at 400 MHz in CDCl₃

Examples 158 to 159

The following compounds, of the general formula shown below, wereprepared using the same method to that described example 55. The productof preparation 101 was treated sequentially with potassium tert-butoxideand either acetylhydrazide to afford example 158 or2-methoxyacetylhydrazide (preparation 5) to afford example 159. Thecrude compounds were triturated with diethyl ether to afford desiredproduct.

No. R¹ R² Data (LRMS) Yield 158

H APCI m/z 382 [M + H]⁺ 29% 159

OCH₃ APCI m/z 412 [M + H]⁺ 31%

Example 1605-[3-[(3S)-3-(2-Chlorophenoxy)pyrrolidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine

5-Isothiocyanato-2-methoxypyridine [(306 mg, 1.84 mmol), J. Org. Chem.(1980), 45, 4219] was added to a solution of the product of preparation91 [(387 mg, 1.95 mmol) and N,N-diisopropylethylamine (0.32 mL, 1.84mmol) in dichloromethane (5 mL) and the mixture was stirred for 1 hourat room temperature. The reaction mixture was then washed with water (5mL), saturated citric acid solution (5 mL) and brine. The organicsolution was dried over magnesium sulfate and concentrated in vacuo.Potassium tert-butoxide (217 mg, 1.93 mmol) was added to a solution ofthe residue in tetrahydrofuran (6 mL) and the reaction was stirred atroom temperature for 15 minutes. Methyl p-toluenesulfonate (360 mg, 1.93mmol) was then added and the mixture was stirred for 45 minutes at roomtemperature. The reaction mixture was concentrated in vacuo andre-dissolved in dichloromethane. The organic solution was washed withsodium hydrogen carbonate solution, dried over magnesium sulfate andconcentrated in vacuo. The residue was re-dissolved in tetrahydrofuran(10 mL), trifluoroacetic acid (67 μL) and 2-methoxyacetylhydrazide (183mg, 1.76 mmol) were added and the mixture was heated under reflux for 2hours. The reaction mixture was then concentrated in vacuo andpartitioned between ethyl acetate and water. The organic solution wasseparated, washed with sodium hydrogen carbonate solution and brine,dried over magnesium sulfate and concentrated in vacuo. Purification ofthe residue by column chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 95:5, afforded the title compound in25% yield, 191 mg.

¹H NMR (400 MHz, CDCl₃) δ: 2.00-2.10 (m, 2H), 3.20-3.60 (m, 7H), 3.98(s, 3H), 4.25 (s, 2H), 4.85-4.90 (m, 1H), 6.78-6.90 (m, 3H), 7.10-7.18(m, 1H), 7.30-7.35 (d, 1H), 7.55-7.60 (d, 1H), 8.20 (s, 1H); APCI m/z416 [M+H]⁺.

Example 1612-Methoxy-5-{3-(methoxymethyl)-5-[(3S)-3-(2-methylphenoxy)pyrrolidin-1-yl]-4H-1,2,4-triazol-4-yl}pyridine

The title compound was prepared from the product of preparation 92,5-Isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219) and2-methoxyacetylhydrazide (preparation 5), using the same method as thatdescribed for example 160, as a foam in 52% yield. LRMS APCI m/z 396[M+H]⁺.

Example 1625-({1-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)-4-methylpyrimidine

The title compound was prepared from the product of preparation 21 and4-methylpyrimidin-5-ol [Chem. Heterocycl. Compd. (Engl. Transl), 1989,25, 530], using the same method as that described for example 37, in 41%yield. LRMS APCI m/z 382 [M+H]⁺.

Example 1635-({1-[5-(Methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)-4-methylpyrimidine

The title compound was prepared from the product of preparation 42 and4-methylpyrimidin-5-ol [Chem. Heterocycl. Compd. (Engl. Transl), 1989,25, 530], using the same method as that described for example 37, in 24%yield. ¹H NMR (400 MHz, CDCl₃) δ: 1.78-1.90 (m, 2H), 1.95-2.10 (m, 2H),2.45 (s, 3H), 3.12-3.25 (m, 2H), 3.32 (s, 3H), 3.38-3.50 (m, 2H), 4.00(s, 3H), 4.35 (s, 2H), 4.50-4.62 (m, 1H), 6.88-6.92 (d, 1H), 7.70-7.76(d, 1H), 8.18 (s, 1H), 8.25-8.30 (s, 1H), 8.70 (s, 1H); LRMS APCI m/z412 [M+H]⁺.

Example 1645-{3-[4-(3,5-Difluoro-2-methylphenoxy)piperidin-1-yl]-5-methyl-4H-1,2,4-triazol-4-yl}-2-methoxypyridine

The title compound was prepared from the product of preparation 21 and68, using the same method as that described for example 37, in 48%yield. ¹H NMR (400 MHz, CDCl₃) δ: 1.70-1.85 (m, 2H), 1.90-2.00 (m, 2H),2.05 (s, 3H), 2.25 (s, 3H), 3.00-3.08 (m, 2H), 3.28-3.38 (m, 2H), 4.00(s, 3H), 4.35-4.40 (m, 1H), 6.30-6.42 (m, 2H), 6.88-6.92 (d, 1H),7.50-7.55 (d, 1H), 8.12 (s, 1H); LRMS APCI m/z 416 [M+H]⁺.

Example 1655-[3-[4-(3,5-Difluoro-2-methylphenoxy)piperidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine

The title compound was prepared from the product of preparation 42 and68, using the same method as that described for example 37, in 32%yield. ¹H NMR (400 MHz, CDCl₃) δ: 1.72-1.85 (m, 2H), 1.90-2.00 (m, 2H),2.05 (s, 3H), 3.05-3.12 (m, 2H), 3.30-3.40 (m, 5H), 4.00 (s, 3H), 4.35(s, 2H), 4.38-4.42 (m, 1H), 6.30-6.42 (m, 2H), 6.87 (d, 1H), 7.67 (d,1H), 8.25 (s, 1H); LRMS APCI m/z 446 [M+H]⁺

Examples 166 to 171

The following compounds, of the general formula shown below, wereprepared using the same method to that described for example 139, usingthe product of preparation 117 with commercially available phenols.

No. R¹ Data (LRMS) Yield 166

APCI m/z 382 [M + H]⁺ 30% 167

APCI m/z 414 [M + H]⁺ 37% 168

APCI m/z 418[M + H]⁺ 38% 169

APCI m/z 414 [M + H]⁺ 38% 170

APCI m/z 432 [M + H]⁺ 41% 171

APCI m/z 434 [M + H]⁺ 41%

Example 1724-Chloro-6-{1-[5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-azetidin-3-yloxy}-5-methyl-pyrimidine

The title compound was prepared from the product of preparation 118 and4,6-dichloro-5-methylpyrimidine, using the same method as that describedfor example 55, in 100% yield.

LRMS APCI m/z 418 [M+H]⁺.

Examples 173 to 177

The following compounds, of the general formula shown below, wereprepared using the same method to that described for example 139, usingthe product of preparation 110 with commercially available phenols.

No. R¹ Data (LRMS) Yield 173

APCI m/z 384 [M + H]⁺ 12% 174

APCI m/z 384 [M + H]⁺ 94% 175

APCI m/z 388 [M + H]⁺ 10% 176

APCI m/z 352 [M + H]⁺ 10% 177

APCI m/z 404 [M + H]⁺ 20%

Example 1785-{3-[3-(2-Chloro-4-fluoro-phenoxy)-azetidin-1-yl]-5-methoxymethyl-[1,2,4]triazol-4-yl}-pyridin-2-ol

Trimethylsilyl iodide (86 μL, 0.29 mmol) was added to a solution of theproduct of example (100 mg, 0.24 mmol) in acetonitrile (5 mL) at roomtemperature. The reaction mixture was then heated at 70° C. for 18 hrsthen cooled to room temperature. The reaction mixture was diluted withEtOAc (20 mL) then washed with 2N (aq) HCl (10 mL) and brine.Purification of the residue by column chromatography on silica gel,eluting with dichloromethane:methanol, 100:0 to 95:5 then neat MeOH thendichloromethane:methanol:NH₃ 100:10:1, afforded the title compound in15% yield, 15 mg. ¹H NMR (400 MHz, CDCl₃) δ: 3.35 (s, 3H), 4.10-4.20 (m,2H), 4.30-4.40 (m, 4H), 4.95-5.00 (m, 1H), 6.50-6.60 (m, 1H), 6.70-6.75(m, 1H), 6.85-6.95 (m, 1H), 7.10-7.20 (m, 1H), 7.50-7.55 (m, 1H),7.65-7.80 (m, 1H), 8.10-8.15 (s, 1H); APCI m/z 406 [M+H]⁺.

The invention claimed is:
 1. A compound of formula (I):

wherein: m is 2 and n is 1; X is selected from O, NH, N(C₁-C₆)alkyl,NC(O)(C₁-C₆)alkyl, N(SO₂(C₁-C₆)alkyl), S and SO₂; R¹ is phenyl ornapthyl wherein said phenyl or napthyl is optionally substituted withone or more substituents independently selected from halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃, NH(C₁-C₆)alkyl,N((C₁-C₆)alkyl)₂, CO(C₁-C₆)alkyl, C(O)O(C₁-C₆)alkyl, C(O)NH(C₁-C₆)alkyl,C(O)N((C₁-C₆)alkyl)₂, C(O)OH and C(O)NH₂; R² is selected from: (i) H andhydroxy; (ii) (C₁-C₆)alkyl, which is optionally substituted byO(C₁-C₆)alkyl or phenyl; (iii) O(C₁-C₆)alkyl, which is optionallysubstituted by O(C₁-C₆)alkyl; (iv) NH(C₁-C₆)alkyl, said alkyl groupbeing optionally substituted by O(C₁-C₆)alkyl; and (v) N((C₁-C₆)alkyl)₂,one or both of said alkyl groups being optionally substituted byO(C₁-C₆)alkyl; R³ is selected from H, (C₁-C₆)alkyl and(C₁-C₆)alkoxy(C₁-C₆)alkyl; R⁴, R⁵, R⁶ and R⁷ are each independentlyselected from H, halo, hydroxy, CN, (C₁-C₆)alkyl, NH(C₁-C₆)alkyl,N((C₁-C₆)alkyl)₂ and O(C₁-C₆)alkyl; R⁸ is selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, CH₂OH, CH₂NH₂, CH₂NH(C₁-C₆)alkyl,CH₂N((C₁-C₆)alkyl)₂, CN, C(O)NH₂, C(O)NH(C₁-C₆)alkyl andC(O)N((C₁-C₆)alkyl)₂; a tautomer thereof or a pharmaceuticallyacceptable salt of said compound or tautomer.
 2. A compound according toclaim 1 wherein X is O; R¹ is phenyl, wherein said phenyl is optionallysubstituted with one to three substituents independently selected fromchloro, fluoro, methyl, ethyl, trifluoromethyl, cyano and methoxy; R² isH, methyl or methoxy; R³ is H or methyl; R⁴, R⁵, R⁶ and R⁷ are eachindependently selected from H, methyl, ethyl, isopropyl, methoxy, cyano,CF3, N(CH₃)₂, C(O)N(CH₃)₂, and C(O)NH₂ or a pharmaceutically acceptablesalt thereof.
 3. A compound according to claim 2 wherein R² and R⁵ areeach methoxy; and R³, R⁴, R6, R⁷ and R⁸ are each H; or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1 wherein X is selected from O, NH, N(C₁-C₃)alkyl, andN(SO₂(C₁-C₃)alkyl).
 5. A compound according to claim 4 wherein X is O orNCH₃; or a pharmaceutically acceptable salt thereof.
 6. A compoundaccording to claim 1 wherein R¹ is phenyl; wherein said phenyl isoptionally substituted with one to three substituents independentlyselected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃, NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂,CO(C₁-C₆)alkyl, C(O)O(C₁-C₆)alkyl, C(O)NH(C₁-C₆)alkyl,C(O)N((C₁-C₆)alkyl)₂, C(O)OH and C(O)NH₂ or a pharmaceuticallyacceptable salt thereof.
 7. A compound according to claim 6 wherein R¹is phenyl; wherein said phenyl is optionally substituted with one tothree substituents independently selected from halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano, CF₃, N((C₁-C₆)alkyl)₂,C(O)N((C₁-C₆)alkyl)₂, and C(O)NH₂; or a pharmaceutically acceptable saltthereof.
 8. A compound according to claim 7 wherein R¹ is phenyl,wherein said phenyl is optionally substituted with one to threesubstituents independently selected from halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, cyano, CF₃, N((C₁-C₆)alkyl)₂, C(O)N((C₁-C₆)alkyl)₂, andC(O)NH₂ or a pharmaceutically acceptable salt thereof.
 9. A compoundaccording to claim 8 wherein R¹ is phenyl, wherein said phenyl isoptionally substituted with one to three substituents independentlyselected from chloro, fluoro, methyl, ethyl, isopropyl, methoxy, cyano,CF₃, N(CH₃)₂, C(O)N(CH₃)₂, and C(O)NH₂; or a pharmaceutically acceptablesalt thereof.
 10. A compound according to claim 1 wherein X is selectedfrom O, NH, N(C₁-C₃)alkyl, and N(SO₂(C₁-C₃)alkyl); or a pharmaceuticallyacceptable salt thereof.
 11. A compound according to claim 10 wherein R¹is phenyl, wherein said phenyl is optionally substituted with one tothree substituents independently selected from chloro, fluoro, methyl,ethyl, isopropyl, methoxy, cyano, CF₃, N(CH₃)₂, C(O)N(CH₃)₂, andC(O)NH₂; or a pharmaceutically acceptable salt thereof.
 12. A compoundaccording to claim 11 wherein R² is selected from: (i) H or hydroxy;(ii) (C₁-C₃)alkyl, which is optionally substituted by O(C₁-C₃)alkyl;(iii) O(C₁-C₃)alkyl, which is optionally substituted by O(C₁-C₃)alkyl;(iv) NH(C₁-C₃)alkyl, said alkyl group being optionally substituted byO(C₁-C₃)alkyl; and (v) N((C₁-C₃)alkyl)₂, one or both of said alkylgroups being optionally substituted by O(C₁-C₃)alkyl; or apharmaceutically acceptable salt thereof.
 13. A compound according toclaim 12 wherein R² is selected from: (i) H or hydroxy; (ii)(C₁-C₃)alkyl, which is optionally substituted by O(C₁-C₃)alkyl; and(iii) O(C₁-C₃)alkyl, which is optionally substituted by O(C₁-C₃)alkyl;or a pharmaceutically acceptable salt thereof.
 14. A compound accordingto claim 13 wherein R³ is H or (C₁-C₃)alkyl; or a pharmaceuticallyacceptable salt thereof.
 15. A compound according to claim 14 whereinR⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halo, hydroxy,(C₁-C₃)alkyl and O(C₁-C₃)alkyl; or a pharmaceutically acceptable saltthereof.
 16. A compound according to claim 15 wherein R⁸ is selectedfrom H, methyl, ethyl, methoxymethyl, methoxyethyl and CN; or apharmaceutically acceptable salt thereof.
 17. A compound according toclaim 1 wherein R² is selected from: (i) H or hydroxy; (ii)(C₁-C₃)alkyl, which is optionally substituted by O(C₁-C₃)alkyl; (iii)O(C₁-C₃)alkyl, which is optionally substituted by O(C₁-C₃)alkyl; (iv)NH(C₁-C₃)alkyl, said alkyl group being optionally substituted byO(C₁-C₃)alkyl; and (v) N((C₁-C₃)alkyl)₂, one or both of said alkylgroups being optionally substituted by O(C₁-C₃)alkyl; or apharmaceutically acceptable salt thereof.
 18. A compound according toclaim 17 wherein R² is selected from: (i) H or hydroxy; (ii)(C₁-C₃)alkyl, which is optionally substituted by O(C₁-C₃)alkyl; and(iii) O(C₁-C₃)alkyl, which is optionally substituted by O(C₁-C₃)alkyl;or a pharmaceutically acceptable salt thereof.
 19. A compound accordingto claim 18 wherein R² is selected from H, hydroxy, methyl, methoxy andethoxy; or a pharmaceutically acceptable salt thereof.
 20. A compoundaccording to claim 1 wherein R³ is H or (C₁-C₃)alkyl; or apharmaceutically acceptable salt thereof.
 21. A compound according toclaim 20 wherein R³ is H or CH₃; or a pharmaceutically acceptable saltthereof.
 22. A compound according to claim 1 wherein R⁴, R⁵, R⁶ and R⁷are each independently selected from H, halo, hydroxy, (C₁-C₃)alkyl andO(C₁-C₃)alkyl; or a pharmaceutically acceptable salt thereof.
 23. Acompound according to claim 22 wherein R⁴ is H or methyl; R⁵ is hydroxyor methoxy; and R⁶ and R⁷ are both H; or a pharmaceutically acceptablesalt thereof.
 24. A compound according to claim 1 wherein R⁸ is selectedfrom H, methyl, ethyl, isopropyl, methoxymethyl, methoxyethyl, CH₂OH,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CN, C(O)NH₂, C(O)NHCH₃, and C(O)N(CH₃)₂;or a pharmaceutically acceptable salt thereof.
 25. A compound accordingto claim 24 wherein R⁸ is selected from H, methyl, ethyl, methoxymethyl,methoxyethyl and CN; or a pharmaceutically acceptable salt thereof. 26.A compound of formula (I):

wherein: m is 2 and n is 1; X is selected from O and N(C₁-C₆)alkyl; R¹is phenyl or napthyl wherein said phenyl or napthyl is optionallysubstituted with one or more substituents independently selected fromhalo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, cyano,CF₃, C(O)N((C₁-C₆)alkyl)₂ and C(O)NH₂; R² is selected from H, hydroxyl,(C₁-C₆)alkyl and O(C₁-C₆)alkyl; R³ is selected from H and (C₁-C₆)alkyl;R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, (C₁-C₆)alkyland O(C₁-C₆)alkyl; R⁸ is selected from H and (C₁-C₆)alkyl; a tautomerthereof or a pharmaceutically acceptable salt of said compound ortautomer.
 27. A pharmaceutical composition comprising a compound offormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable diluent or carrier.
 28. Amethod of treating premature ejaculation, preterm labor, or benignprostatic hyperplasia, in a mammal in need of treatment thereof, themethod comprising administering to said mammal a therapeuticallyeffective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 29. A method of treatingpremature ejaculation, preterm labor, or benign prostatic hyperplasia,in a mammal in need of treatment thereof, the method comprisingadministering to said mammal a therapeutically effective amount of acompound according to claim 26 or a pharmaceutically acceptable saltthereof.
 30. The method according to claim 29 wherein preterm labor orbenign prostatic hyperplasia is treated.